Bicyclic heterocycles as FGFR4 inhibitors

ABSTRACT

The present disclosure relates to bicyclic heterocycles of Formula (I′), and pharmaceutical compositions of the same, that are inhibitors of the FGFR3 and/or FGFR4 enzyme and are useful in the treatment of FGFR-associated diseases.

FIELD OF THE INVENTION

The present disclosure relates to bicyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of the FGFRenzymes and are useful in the treatment of FGFR-associated diseases suchas cancer.

BACKGROUND OF INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

Aberrant activation of this pathway either through overexpression of FGFligands or FGFR or activating mutations in the FGFRs can lead to tumordevelopment, progression, and resistance to conventional cancertherapies. In human cancer, genetic alterations including geneamplification, chromosomal translocations and somatic mutations thatlead to ligand-independent receptor activation have been described.Large scale DNA sequencing of thousands of tumor samples has revealedthat components of the FGFR pathway are among the most frequentlymutated in human cancer. Many of these activating mutations areidentical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore,development of inhibitors targeting FGFR may be useful in the clinicaltreatment of diseases that have elevated FGF or FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

The FGFR4-FGF19 signaling axis, specifically, has been implicated in thepathogenesis of a number of cancers including hepatocellular carcinoma(Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). Ectopic expression ofFGF19 in transgenic mice was shown to lead to tumor formation in theliver and a neutralizing antibody to FGF19 was found to inhibit tumorgrowth in mice. In addition, overexpression of FGFR4 has been observedin a multiple tumor types including hepatocellular carcinoma,colorectal, breast, pancreatic, prostate, lung, and thyroid cancers.Furthermore, activating mutations in FGFR4 have been reported inrhabdomyosarcoma (Taylor et al. JCI 2009, 119:3395). Targeting FGFR withselective small molecule inhibitors may therefore prove beneficial inthe treatment of cancers and other diseases.

SUMMARY OF INVENTION

In one aspect, the present disclosure relates to compounds havingFormula (I′):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising a compound of Formula (I′), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.

In another aspect, the present disclosure provides methods forinhibiting an FGFR3 and/or FGFR4 enzyme. The method includes contactingthe enzyme with a compound of Formula (I′), or a pharmaceuticallyacceptable salt thereof or a composition comprising compounds of Formula(I′).

In another aspect, the present disclosure provides a method for treatinga disease associated with abnormal activity or expression of an FGFRenzyme, such as an FGFR3 and/or an FGFR4. The method includesadministering an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula (I′), to a patient in need thereof.

In yet another aspect, the present disclosure provides compounds ofFormula (I′) for use in treating a disease associated with abnormalactivity or expression of an FGFR3 and/or FGFR4 enzyme.

In another aspect, the present disclosure provides a method for treatinga disorder mediated by an FGFR3 and/or FGFR4 enzyme, or a mutantthereof, in a patient in need thereof. The method includes administeringto the patient a compound as described herein or pharmaceuticallyacceptable salts thereof or a composition comprising a compound asdescribed herein.

In another aspect, the present disclosure provides the use of compoundsof Formula (I′) in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION

Compounds

In one aspect, the present disclosure provides a compound having Formula(I′):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a C₆₋₁₀ aryl or 5- to 10-membered heteroaryl having carbon and1 to 4 heteroatoms as ring members selected from O, N, and S, whereinthe N and S are each optionally oxidized;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(—NR^(a))NR^(a)R^(a), NR^(a)C(—NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

or two adjacent R¹² substituents on ring A taken together with the atomsto which they are attached form a fused 5- or 6-membered cycloalkylring, 5 to 6-membered heterocycloalkyl ring, phenyl or 5 to 6-memberedheteroaryl ring, wherein the heterocycloalkyl or heteroaryl has 1-2heteroatoms as ring members selected from O, N, and S;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- of R^(a) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(d) substituents;

or any two R^(a) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c), and S(O)₂NR^(c)R^(c); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

or any two R^(c) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e);

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g),OC(O)R^(g), OC(O)NR^(g)R^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g);

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(i), SR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR′C(O)R^(i),NR′C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl of R^(h) are optionally substituted by1, 2, or 3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(i), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)2R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(e), R^(g), R^(i) or R^(k) is independently selected from H, C₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₄ alkenyl or C₂₋₄ alkynyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

or any two R^(e) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

X¹ is —CR¹⁰R¹¹— or —NR⁷—

X² is N or CR⁶;

R¹³ is H, CN, NR^(c4)R^(d4), OR¹ or —C(O)NHR^(e), wherein R¹ is C₁₋₃alkyl or C₁₋₃ haloalkyl;

R² is H, halo, alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R¹⁴ is H, CN, NR^(c4)R^(d4), OR⁴ or —C(O)NHR^(g), wherein R⁴ is C₁₋₃alkyl or haloalkyl;

R⁵ is H, halo, alkyl, C₁₋₃ haloalkyl, CN, or alkoxy;

R⁶ is selected from H, halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 memberedheteroaryl having carbon and 1, 2, or 3 heteroatoms independentlyselected from N, O and S, and a 4-7 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R⁶ are each optionally substituted with 1, 2, or 3substituents independently selected from R^(10A);

R⁷ is selected from H, C(O)NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 5- to 10-membered heteroarylhaving carbon and 1, 2, or 3 heteroatoms independently selected from N,O and S, 4- to 10-membered heterocycloalkyl having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5- to10-membered heteroaryl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- groups of R⁷are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(10A); or two R^(10A) substituentsattached to the adjacent ring atoms of the aryl or heteroaryl ring ofR⁷, taken together with the atoms to which they are attached, form afused C₅₋₆ cycloalkyl ring or a fused 5- to 6-membered heterocycloalkylring having 1-2 heteroatoms as ring members independently selected fromO, N and S, wherein the nitrogen and sulfur atoms are each optionallyoxidized and the fused C₅₋₆ cycloalkyl ring or fused 5 to 6-memberedheterocycloalkyl is optionally substituted with 1 or 2 independentlyselected R¹⁹ groups;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, or 3, R^(10A);

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)²R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹; alternatively, R^(c4) and R^(d4)together with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group which is optionallysubstituted with 1, 2 or 3 substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl; wherein theC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄haloalkyl of R¹⁹ are each further optionally substituted with 1 or 2 R²⁰substituents independently selected from H, halo, CN, NO₂, OR^(q),SR^(q), C(O)R^(q), C(O)NR^(q)R^(q), C(O)OR^(q), OC(O)R^(q),OC(O)NR^(q)R^(q), NR^(q)R^(q), NR^(q)C(O)R^(q), NR^(q)C(O)OR^(q),NR^(q)C(O)NR^(q)R^(q), NR^(q)S(O)R^(q), NR^(q)S(O)₂R^(q),NR^(q)S(O)₂NR^(q)R^(q), S(O)R^(q), S(O)NR^(q)R^(q), S(O)₂R^(q),S(O)₂NR^(q)R^(q), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyland C₁₋₄ haloalkyl, wherein each R^(q) is independently H or C₁₋₄alkyl;

each R^(a9), R^(c9), and R^(d9) is independently selected from H andC₁₋₄ alkyl;

each R^(b9) is independently C₁₋₄ alkyl; and

the subscript n is 0, 1, 2 or 3.

In some embodiments, the present disclosure provides a compound havingFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a C₆₋₁₀ aryl or 5 to 6-membered heteroaryl having carbon and 1to 4 heteroatoms as ring members selected from O, N, and S;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

or two adjacent R¹² substituents on ring A taken together with the atomsto which they are attached form a fused 5- or 6-membered cycloalkylring, 5- to 6-membered heterocycloalkyl ring, phenyl or 5 to 6-memberedheteroaryl ring, wherein the heterocycloalkyl or heteroaryl has 1-2heteroatoms as ring members selected from O, N, and S;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(a) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(d) substituents;

or any two R^(a) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), and S(O)₂NR^(c)R^(c);

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

or any two R^(c) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, wherein the C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl as R^(h) is optionally substituted with 1, 2, or 3independently selected R^(j) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e);

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g),OC(O)R^(g), OC(O)NR^(g)R^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g);

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(i), SR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or3 independently selected R^(j) substituents;

each R is independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,CN, OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(i), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(e), R^(g), R^(i) or R^(k) is independently selected from H, C₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₄ alkenyl or C₂₋₄ alkynyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

or any two R^(e) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

X¹ is —CR¹⁰R¹¹— or —NR⁷—

X² is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶ and R⁷ are each independently selected from H, halo, CN, OR^(a4),SR^(a4), C(O)NR^(c4)R^(d4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl having carbon and 1, 2, or 3 heteroatoms independentlyselected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl groups of R⁶ and R⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A);

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, or 3, R^(10A);

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4)NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, and C₁₋₄ haloalkyl; wherein theC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, and C₁₋₄haloalkyl are each further optionally substituted with 1 or 2 R²⁰substituents independently selected from H, halo, CN, NO₂, OR^(q),SR^(q), C(O)R^(q), C(O)NR^(q)R^(q), C(O)OR^(q), OC(O)R^(q),OC(O)NR^(q)R^(q), NR^(q)R^(q), NR^(q)C(O)R^(q), NR^(q)C(O)OR^(q),NR^(q)C(O)NR^(q)R^(q), NR^(q)S(O)R^(q), NR^(q)S(O)₂R^(q),NR^(q)S(O)₂NR^(q)R^(q), S(O)R^(q), S(O)NR^(q)R^(q), S(O)₂R^(q),S(O)₂NR^(q)R^(q), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl, wherein each R^(q) is independently H orC₁₋₄alkyl;

each R^(a9), R^(c9), and R^(d9) is independently selected from H andC₁₋₄ alkyl;

each R^(b9) is independently C₁₋₄ alkyl; and

the subscript n is 0, 1, 2 or 3.

In some embodiments of compounds of Formula (I′) or (I):

ring A is a C₆₋₁₀ aryl or 5 to 6-membered heteroaryl having carbon and 1to 4 heteroatoms as ring members selected from O, N, and S;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

or two adjacent R¹² substituents on ring A taken together with the atomsto which they are attached form a fused 5- or 6-membered cycloalkylring, 5 to 6-membered heterocycloalkyl ring, phenyl or 5 to 6-memberedheteroaryl ring, wherein the heterocycloalkyl or heteroaryl have 1-2heteroatoms as ring members selected from O, N, and S;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- as R^(a) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(d) substituents;

or any two R^(a) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), and S(O)₂NR^(c)R^(c);

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

or any two R^(c) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e);

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g),OC(O)R^(g), OC(O)NR^(g)R^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g);

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(i), SR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(i), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(e), R^(g), R^(i) or R^(k) is independently selected from H, C₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₄ alkenyl or C₂₋₄ alkynyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

or any two R^(e) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

X¹ is —CR¹⁰R¹¹— or —NR⁷—

X² is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶ is selected from H, halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl having carbon and 1, 2, or 3 heteroatoms independentlyselected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl groups of R⁶ are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R^(10A);

R⁷ is selected from H, C(O)NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylhaving carbon and 1, 2, or 3 heteroatoms independently selected from N,O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1,2, or 3 heteroatoms independently selected from N, O and S; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R⁷ areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10A);

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, or 3, R^(10A);

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl; wherein C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl areeach further optionally substituted with 1 or 2 R²⁰ substituentsindependently selected from H, halo, CN, NO₂, OR^(q), SR^(q), C(O)R^(q),C(O)NR^(q)R^(q), C(O)OR^(q), OC(O)R^(q), OC(O)NR^(q)R^(q), NR^(q)R^(q),NR^(q)C(O)R^(q), NR^(q)C(O)OR^(q), NR^(q)C(O)NR^(q)R^(q),NR^(q)S(O)R^(q), NR^(q)S(O)₂R^(q), NR^(q)S(O)₂NR^(q)R^(q), S(O)R^(q),S(O)NR^(q)R^(q), S(O)₂R^(q), S(O)₂NR^(q)R^(q), C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl, wherein each R^(q) isindependently H or C₁₋₄alkyl

each R^(a9), R^(c9), and R^(d9) is independently selected from H andC₁₋₄ alkyl;

each R^(b9) is independently C₁₋₄ alkyl; and

the subscript n is 0, 1, 2 or 3.

In one aspect, the present disclosure provides a compound having Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a C₆₋₁₀ aryl or 5 to 6-membered heteroaryl having carbon and 1to 4 heteroatoms as ring members selected from O, N, and S;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b)substituents;

or two adjacent R¹² substituents on ring A taken together with the atomsto which they are attached form a fused 5- or 6-membered cycloalkylring, 5 to 6-membered heterocycloalkyl ring, phenyl or 5 to 6-memberedheteroaryl ring, wherein the heterocycloalkyl or heteroaryl have 1-2heteroatoms as ring members selected from O, N, and S;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- as R^(a) are each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(d) substituents;

or any two R^(a) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c)NR^(c)C(O)OR^(c) NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), and S(O)₂NR^(c)R^(c);

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(f) substituents;

or any two R^(c) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, wherein the C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl as R^(h) is optionally substituted with 1, 2, or 3independently selected R^(j) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e);

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, CN, OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g),OC(O)R^(g), OC(O)NR^(g)R^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R, NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g);

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(i), SR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or3 independently selected R^(j) substituents;

each R^(j) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(i), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

each R^(e), R^(g), R^(i) or R^(k) is independently selected from H, C₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₄ alkenyl or C₂₋₄ alkynyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

or any two R^(e) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

X¹ is —CR¹⁰R¹¹— or —NR⁷—

X² is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶ and R⁷ are each independently selected from H, halo, CN, OR^(a4),SR^(a4), C(O)NR^(c4)R^(d4) OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl having carbon and 1, 2, or 3 heteroatoms independentlyselected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl groups of R⁶ and R⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A);

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, or 3, R^(10A);

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

each R^(a9), R^(c9), and R^(d9) is independently selected from H andC₁₋₄ alkyl;

each R^(b9) is independently C₁₋₄ alkyl; and

the subscript n is 0, 1, 2 or 3.

In some embodiments, R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 memberedheteroaryl having carbon and 1, 2, or 3 heteroatoms independentlyselected from N, O and S, and a 4-7 membered heterocycloalkyl moietyhaving carbon and 1, 2, or 3 heteroatoms independently selected from N,O and S; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl groups of R⁷ are each optionally substituted with 1, 2,or 3 substituents independently selected from R^(10A).

In some embodiments, R⁷ is C₁₋₆ alkyl, phenyl, benzyl, C₃₋₆ cycloalkyl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, 4- to 10-membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, 5- to 10-membered heteroaryl, or(5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, each of which is optionallysubstituted with 1, 2, or 3 independently selected R^(10A) substituents;or two R^(10A) substituents attached to the adjacent ring atoms of thearyl or heteroaryl ring of R⁷ are optionally taken together with theatoms to which they are attached form a fused C₅₋₆ cycloalkyl ring or afused 5 to 6-membered heterocycloalkyl ring having 1-2 heteroatoms asring members independently selected from O, N and S, wherein thenitrogen and sulfur atoms are each optionally oxidized and the fusedC₅₋₆ cycloalkyl ring or fused 5 to 6-membered heterocycloalkyl isoptionally substituted with 1 or 2 independently selected R¹⁹ groups.

R⁷ is C₁₋₆ alkyl, cyclopropylmethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4-fluorobenzyl, tetrahydrofuran-3-yl,(3-methylisoxazol-5-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl,(5-cyclopropylisoxazol-3-yl)methyl, 5-methylisoxazol-3-yl)methyl,4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, benzothiazol-6-yl,1-methyl-5-oxopyrrolidin-3-yl, 1-acetylpiperidin-4-yl,2,3-dihydro-1,4-benzodioxin-6-ylmethyl,1-t-butoxycarbonylpiperidin-4-yl, 4-cyanophenyl, 4-pyrimidinyl,2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl,1-methylpyrazol-4-yl, (1,5-dimethylpyrazol-4-yl)methyl, or(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In some embodiments, R⁷ is C₁₋₆ alkyl, cyclopropylmethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorobenzyl,(3-methylisoxazol-5-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl,4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, 1-acetylpiperidin-4-yl,2,3-dihydro-1,4-benzodioxin-6-ylmethyl,1-t-butoxycarbonylpiperidin-4-yl, 4-cyanophenyl, 4-pyrimidinyl,2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl,(1,5-dimethylpyrazol-4-yl)methyl, or(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In some embodiments, R⁷ is C₁₋₆ alkyl, cyclopropylmethyl, cyclopentyl,4-fluorobenzyl, tetrahydrofuran-3-yl, (3-methylisoxazol-5-yl)methyl,(tetrahydro-2H-pyran-4-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl,5-methylisoxazol-3-yl)methyl, 4-fluorophenyl,(1-ethylpyrazol-4-yl)methyl, benzothiazol-6-yl,1-methyl-5-oxopyrrolidin-3-yl, 1-acetylpiperidin-4-yl,2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 4-cyanophenyl, 4-pyrimidinyl,(1,5-dimethylpyrazol-4-yl)methyl, or(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In some embodiments, R⁷ is methyl, isopropyl, pyridazin-4-yl,(2-methoxypyridin-4-yl)methyl, (6-methoxypyridin-3-yl)methyl,3-cyanophenyl, pyrimidin-5-yl, isoquinolin-7-yl,4-methylcarbamoylbenzyl, (5-ethylisoxazol-3-yl)methyl,pyrimidin-4-ylmethyl, 3-cyano-4-fluorophenyl,(5-ethyl-1,3,4-oxadiazol-2-yl)methyl, (2-methylpyridin-4-yl)methyl,pyridin-4-ylmethyl, pyrazin-2-yl, 1-(methylsulfonyl)piperidin-4-yl,(1-methyl-1H-pyrazol-4-yl)methyl, 3,4-difluorobenzyl, 2-cyano-5-pyridyl,2-methylbenzo[d]oxazol-6-yl, 4-(1H-pyrazol-1-yl)phenyl,3-cyano-5-fluorophenyl, 5-cyano-2-pyridyl, oxazol-5-ylmethyl,4-cyano-5-methoxyphenyl, (5-methyloxazol-2-yl)methyl, cyclopropyl,pyrimidin-5-ylmethyl, pyrazin-2-ylmethyl, pyridin-3-yl,6-methylpyrazin-2-yl, pyridazin-3-ylmethyl,3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl, 1-cyanocyclopropyl, 2-pyridyl,(5-isopropylisoxazol-3-yl)methyl, pyridin-2-ylmethyl,(2-methylthiazol-4-yl)methyl, (1-methyl-5-oxopyrrolidin-3-yl)methyl,4-(cyanomethyl)phenyl, 4-(methylsulfonyl)phenyl, 3-fluorophenyl,1-methyl-1H-pyrazol-3-yl, (1,3-dimethyl-1H-pyrazol-4-yl)methyl,3,4-difluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl, pyrimidin-2-yl,5-ethylpyrazin-2-yl, 5-methylpyrazin-2-yl, (tetrahydrofuran-3-yl)methyl,3-methoxyphenyl, 2-fluorophenyl, 3-(methylsulfamoyl)phenyl,5-methoxypyrazin-2-yl, 4-(dimethylcarbamoyl)phenyl,2-(1-methyl-1H-pyrazol-4-yl)ethyl, 5-methyl-1,3,4-oxadiazol-2-yl,(2-ethoxypyridin-4-yl)methyl,(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl,(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl, 2-oxoindolin-5-yl,2-methyl-3-oxoisoindolin-5-yl, (2-methylpyrimidin-4-yl)methyl,1-(methylcarboxy)piperidin-4-yl, 4-(methoxycarbonylamino)phenyl,(1-cyclopropyl-1H-pyrazol-4-yl)methyl,(1-cyanomethyl-1H-pyrazol-4-yl)methyl,(1-cyclopropylmethyl-1H-pyrazol-4-yl)methyl,(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl, 1H-pyrazol-4-yl,1-cyclopropyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-propyl-1H-pyrazol-4-yl, 1H-indazol-6-yl, 1H-indazol-5-yl,pyrimidin-4-yl, cyclobutyl, 3-pyridyl, 2-methoxyethyl,cyclopropylmethyl, ethyl, 4-cyanophenyl,(1-ethyl-1H-pyrazol-4-yl)methyl, (5-methyl-1,3,4-oxadiazol-2-yl)methyl,or 1-methyl-1H-pyrazol-4-yl.

In some embodiments, compounds of Formula (I′) or (I) have selectiveinhibitory activity on FGFR4 enzyme or any mutant thereof over otherFGFR enzymes. In other embodiments, compounds of Formula (I′) or (I)have selective inhibitory activity on FGFR3 enzyme or any mutant thereofover other FGFR enzymes. In other embodiments, compounds of Formula (I′)or (I) have selective dual inhibitory activity on both FGFR3 and FGFR4enzymes or any mutant thereof.

In some embodiments of compounds of Formula (I′) or (I), ring A is C₆₋₁₀aryl. In certain instances, ring A is phenyl. In one instance, ring A is1-naphthyl or 2-naphthyl.

In some embodiments of compounds of Formula (I′) or (I), ring A isphenyl and two adjacent R¹² substituents on the phenyl ring takentogether with the carbon atoms to which they are attached form a fused 3to 7-membered cycloalkyl. In some instances, ring A is phenyl and twoadjacent R¹² substituents on the phenyl ring taken together with thecarbon atoms to which they are attached form a fused cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments of compounds of Formula (I′) or (I), ring A isphenyl and two adjacent R¹² substituents on the phenyl ring takentogether with the carbon atoms to which they are attached form a fused 4to 6-membered heterocycloalkyl. In some instances, ring A is phenyl andtwo adjacent R¹² substituents on the phenyl ring taken together with thecarbon atoms to which they are attached form a fused 2-oxetanyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 1,1-dioxotetrahydrothiophen-2-yl,1,1-dioxotetrahydrothiophen-3-yl, 2-tetrahydropyranyl,3-tetrahydropyranyl, 4-tetrahydropyranyl, 3,6-dihydro-2H-pyranyl,3,4-dihydro-2H-pyranyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl,2-oxo-pyrrolidin-3-yl, 2-oxo-pyrrolidin-4-yl, 2-oxo-pyrrolidin-5-yl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-oxo-piperidin-1-yl, 2-oxo-piperidin-3-yl, 2-oxo-piperidin-4-yl,2-oxo-piperidin-5-yl, 2-oxo-piperidin-6-yl, 1-piperazinyl,2-piperazinyl, 4-morpholinyl, 3-morpholinyl or 2-morpholinyl.

In some embodiments of compounds of Formula (I′) or (I), ring A is5-membered heteroaryl. In some embodiments, ring A is 5-memberedheteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, thiophenyl, thiazolyl, isoxazolyl, isothiazolyl,or furanyl. In some embodiments, ring A is pyrazolyl or imidazolyl. Insome embodiments, ring A is pyrazolyl. In some embodiments, ring A is4-pyrazolyl.

In some embodiments of compounds of Formula (I′) or (I), ring A is5-membered heteroaryl selected from 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl,1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl,1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol-4-yl,1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl,1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl,1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl,3-furanyl, 2-thiophenyl, and 3-thiophenyl.

In some embodiments of compounds of Formula (I′) or (I), ring A is6-membered heteroaryl. In certain embodiments, ring A is selected frompyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. In someembodiments of compounds of Formula (I′) or (I), ring A is 6-memberedheteroaryl selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, and1,2,4-triazin-6-yl.

In some embodiments, ring A is pyridyl. In other embodiments, ring A isphenyl or 6-membered heteroaryl. In other embodiments, ring A is phenylor pyridyl.

In some embodiments, ring A is

each of which is optionally substituted with 1 or 2 R¹² substituents asdefined herein.

In some embodiments, ring A is

substituted with R¹² as defined herein.

In some embodiments, ring A is

optionally substituted with R¹².

In some embodiments, ring A is

In some embodiments, ring A is

optionally substituted with R¹².

In some embodiments, ring A is

In some embodiments of compounds of Formula (I′), R¹³ is H, CN,NR^(c4)R^(d4), OR¹ or —C(O)NHR^(e), wherein R¹ is C₁₋₃ alkyl or C₁₋₃haloalkyl and R¹⁴ is H, CN, NR^(c4)R^(d4), OR⁴ or —C(O)NHR^(g), whereinR⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl. In other embodiments, R¹³ is OR¹ andR¹⁴ is OR⁴. In other embodiments, R¹³ is —C(O)NHR^(e) and R¹⁴ is OR⁴. Inother embodiments, R¹³ and R¹⁴ are each OCH₃. In other embodiments, R¹³is —C(O)NHR^(e) and R¹⁴ is OR⁴. In some embodiments, R¹³ and R¹⁴ areeach independently selected form C₁₋₄ alkyl-NHC(O)— and OCH₃. In oneembodiment, R¹³ is —C(O)NHC₁₋₆ alkyl and R¹⁴ is OR⁴. In anotherembodiment, R¹³ is —C(O)NHC₁₋₆alkyl and R¹⁴ is OCH₃. In anotherembodiment, R¹³ is —C(O)NHCH₃ and R¹⁴ is OCH₃. In some embodiments, R¹³is H and R¹⁴ is CN, NR^(c4)R^(d4), OR⁴ or —C(O)NHR^(g).

In some embodiments of compounds of Formula (I′) or (I), R² and R⁵ areeach independently H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃alkoxy. In other embodiments, R² and R⁵ are each independently halogen.In some instances, R² and R⁵ are halogen. In a preferred embodiment, R²and R⁵ are F.

In some embodiments of compounds of Formula (I′) or (I), R¹ and R⁴ areeach independently C₁₋₃ alkyl or C₁₋₃ haloalkyl. In some instances, R¹and R⁴ are each independently C₁₋₃ alkyl. In other instances, R¹ and R⁴are each independently methyl, ethyl, propyl, CF₃, CF₂H or CFH₂. In apreferred embodiment, R¹ and R⁴ are CH₃.

In some embodiments of compounds of Formula (I′) or (I), R³ is H, halo,C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy. In some instances, R³ isH, F, Cl, C₁₋₃alkyl, CF₃, CF₃O, CFH₂, CHF₂, OCFH₂ or OCHF₂. In apreferred embodiment, R³ is H.

In some embodiments of compounds of Formula (I′) or (I), R¹⁰ and R¹¹ areeach independently C₁₋₆ alkyl. In some instances, R¹⁰ and R¹¹ aremethyl. In some embodiments, R¹⁰ and R¹¹ taken together with the carbonatom to which they are attached form a 3-, 4-, 5-, 6-, or 7-memberedcycloalkyl group, which is optionally substituted with 1 or 2independently selected R^(10A) groups. In some instances, R¹⁰ and R¹¹taken together with the carbon atom to which they are attached formcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each ofwhich is optionally substituted with from 1-3 R^(10A) groups. In apreferred embodiment, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl, optionally substituted with 1 or 2independently selected R^(10A) groups. In some embodiments, R¹⁰ and R¹¹are H. In certain embodiments, R¹⁰ and R¹¹ are each independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from R^(10A).

In some embodiments of compounds of Formula (I′) or (I), R¹⁰ and R¹¹taken together with the carbon atom to which they are attached form 4-,5-, 6-, or 7-membered heterocycloalkyl group, which is optionallysubstituted with 1 or 2 independently selected R^(10A) groups. In someinstances, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form 2-oxetanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 1-azetidinyl,2-azetidinyl, 3-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 4-morpholinyl,3-morpholinyl or 2-morpholinyl, 1-azepanyl, 2-azepanyl, 3-azepanyl,4-azepanyl, 2-oxepanyl, 3-oxepanyl or 4-oxepanyl, each of which isoptionally substituted with 1 or 2 independently selected R^(10A).

In some embodiments, R^(10A) is halo, CN, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—C(O)R^(b4), or —C(O)OR^(b4); or two R^(10A) substituents attached tothe adjacent ring atoms of the aryl or heteroaryl ring of R⁷ areoptionally taken together with the atoms to which they are attached forma 5- to 6-membered heterocycloalkyl ring having 1-2 heteroatoms as ringmembers independently selected from O, N and S, wherein the nitrogen andsulfur atoms are each optionally oxidized.

In some embodiments, R^(10A) is F, Cl, CH₃, C₁₋₆ alkyl, CN, —C(O)C₁₋₄alkyl or —C(O)OC₁₋₄ alkyl; or two R^(10A) substituents attached to theadjacent ring atoms of the aryl or heteroaryl ring of R⁷ are optionallytaken together with the atoms to which they are attached form atetrahydrofuran, tetrahydropyran, 1,4-dioxane, morpholine,tetrahydrothiopyran or tetrahydrothiophene ring, each of which isoptionally substituted with 1 or 2 R¹⁹ substituents.

In some embodiments, R^(10A) is F, CH₃, CN, —C(O)CH₃, or cyclopropyl.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl.

In some embodiments of compounds of Formula (I′) or (I), X¹ is —CR¹⁰R¹¹—or —NR⁷—. In one embodiment, X¹ is —CR¹⁰R¹¹—. In another embodiment, X¹is —NR⁷—. In some instances, X¹ is CH₂ or NH.

In some embodiments of compounds of Formula (I′) or (I), X¹ is NR⁷,wherein R⁷ is C₁₋₆ alkyl, phenyl, benzyl, C₃₋₆ cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, 4- to 10-membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, 5- to 10-membered heteroaryl, or(5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, each of which is optionallysubstituted with 1, 2, or 3 independently selected R^(10A) substituents;or two R^(10A) substituents attached to the adjacent ring atoms of thearyl or heteroaryl ring of R⁷ are taken together with the atoms to whichthey are attached form a fused C₅₋₆ cycloalkyl ring or a fused 5 to6-membered heterocycloalkyl ring having 1-2 heteroatoms as ring membersindependently selected from O, N and S, wherein the nitrogen and sulfuratoms are each optionally oxidized; and wherein one or two ring atoms inthe fused C₅₋₆ cycloalkyl ring or fused 5 to 6-membered heterocycloalkylare optionally replaced by a carbonyl group, and the fused C₅₋₆cycloalkyl ring or fused 5 to 6-membered heterocycloalkyl is optionallysubstituted with 1 or 2 independently selected R¹⁹ groups. In someinstances, R^(10A) is halo, CN, C₁₋₆alkyl, C₃₋₆cycloalkyl, —C(O)R^(b4)or —C(O)OR^(b4); or two R^(10A) substituents attached to the adjacentring atoms of the aryl or heteroaryl ring of R⁷ are taken together withthe atoms to which they are attached form a 5- to 6-memberedheterocycloalkyl ring having 1-2 heteroatoms as ring membersindependently selected from O, N and S, wherein the nitrogen and sulfuratoms are each optionally oxidized. In other instances, R^(10A) is F,Cl, CH₃, C₁₋₆ alkyl, CN, —C(O)C₁₋₄ alkyl or —C(O)OC₁₋₄ alkyl; or twoR^(10A) substituents attached to the adjacent ring atoms of the aryl orheteroaryl ring of R⁷ are taken together with the atoms to which theyare attached form a tetrahydrofuran, tetrahydropyran, 1,4-dioxane,morpholine, tetrahydrothiopyran, or tetrahydrothiophene ring, each ofwhich is optionally substituted with 1 or 2 R¹⁹ substituents.

In some embodiments of compounds of Formula (I′) or (I), X¹ is NR⁷,wherein R⁷ is C₁₋₆ alkyl, cycloproprylmethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4-fluorobenzyl, (3-methylisoxazol-5-yl)methyl,(5-cyclopropylisoxazol-3-yl)methyl, 4-fluorophenyl,(1-ethylpyrazol-4-yl)methyl, 1-acetylpiperidin-4-yl,2,3-dihydro-1,4-benzodioxin-6-ylmethyl,1-t-butoxycarbonylpiperidin-4-yl, 4-cyanophenyl, 4-pyrimidinyl,2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl,(1,5-dimethylpyrazol-4-yl)methyl or(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In some embodiments of compounds of Formula (I′) or (I), X² is N or CR⁶.In other embodiments, X² is N or CH. In one preferred embodiment, X² isN. In another preferred embodiment, X² is CH.

In some embodiments of compounds of Formula (I′) or (I), each R¹² isindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OR^(a), SR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2or 3 R^(b) substituents.

In some embodiments, each R¹² is independently selected from F, Cl, CN,CH₃, CH₂CH₃, NH₂, OCH₃, —C(O)NH(C₁₋₄ alkyl), NHC(O)CH₃, NHS(O)₂CH₃,NHS(O)₂R^(a), C(O)R^(a), CH₂C(O)R^(a), —CH₂CH₂R^(a), morpholinosulfonyl,imidazolyl, 4-morpholinyl, (3-cyanopyrrolidin-1-yl)methyl,2-cyanoprop-2-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, benzyl,pyridylmethyl, 1,1-dioxothiolan-3-yl, 1-methylsulfonylazetidin-3-yl,1-acetyl-3-(cyanomethyl)azetidin-3-yl, and —CH₂-(4-morpholinyl), whereinR^(a) is 4-morpholinyl.

In some embodiments, each R¹² is independently selected from F, Cl, CN,CH₃, CH₂CH₃, NH₂, —C(O)NH(C₁₋₄ alkyl), NHC(O)CH₃, NHS(O)₂CH₃, C(O)R^(a),—CH₂C(O)R^(a), —CH₂CH₂R^(a), morpholinosulfonyl, imidazolyl,4-morpholinyl, (3-cyanopyrrolidin-1-yl)methyl, 2-cyanoprop-2-yl,1-cyanocyclobutyl, pyridylmethyl, 1,1-dioxothiolan-3-yl,1-acetyl-3-(cyanomethyl)azetidin-3-yl, and —CH₂-(4-morpholinyl), whereinR^(a) is 4-morpholinyl.

In some embodiments of compounds of Formula (I′) or (I), each R¹² isindependently NH₂, CH₃, F, CN, 1-piperidinyl, 1-piperazinyl. or4-morpholinyl.

In some embodiments, each R¹² is independently selected from —NH₂,—NHOH, —NHOR^(a), —NHR^(a), —NHC(O)R^(a), —NHC(O)NHR^(a), —NHS(O)₂R^(a),—C(O)R^(a), —S(O)₂R^(a), C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₄haloalkoxy, halo, CN, C₃₋₆cycloalkyl, phenyl-C₁₋₄alkyl, 5-6 memberedheteroaryl, 5- to 6-membered heteroaryl-C₁₋₄alkyl, 4 to 6-memberedheterocycloalkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,wherein the C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl-C₁₋₄alkyl, 5-6 memberedheteroaryl, 4 to 6-membered heterocycloalkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with from 1-3R^(b); and C₁₋₆ alkoxy or C₁₋₄ haloalkoxy is optionally substituted by1-3 R^(d).

In some embodiments, each R¹² is independently F, Cl, CN, CH₃, NH₂,OCH₃, NHS(O)₂R^(a), C(O)R^(a), —CH₂C(O)R^(a), imidazoyl, 4-morpholinyl,—CH₂-(4-morpholinyl), (3-cyanopyrrolidin-1-yl)methyl,1-cycano-1-methyl-ethyl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, benzyl,1,1-dioxothiolan-3-yl, 1-methylsulfonylazetidin-3-yl,1-acetyl-3-(cyanomethyl)azetidin-3-yl and —CH₂-(4-morpholinyl), whereinR^(a) is 4-morpholinyl.

In some embodiments, each R¹² is independently F, Cl, CN, CH₃, NH₂,OCH₃, NHS(O)₂R^(a), C(O)R^(a), imidazoyl, 4-morpholinyl, and—CH₂-(4-morpholinyl), wherein R^(a) is 4-morpholinyl.

In some embodiments, R¹² is H, methyl, ethyl, CN, cyanomethyl,2-cyanoethyl, 1-cyanocyclobutyl, 3-morpholinopropyl,1-(methylsulfonyl)pyrrolidin-3-yl,(1-(methylsulfonyl)piperidin-4-yl)ethyl, (4-methoxypiperidin-1-yl)ethyl,2-morpholinoethyl, 2-morpholino-2-oxoethyl, dimethylamino,(3-methoxypyrrolidin-1-yl)ethyl, (1,1-dioxido-1,2-thiazinan-3-yl)methyl,1-methylpyrrolidin-3-yl, (dimethylamino)ethyl, 2-(piperidin-4-yl)ethyl,(1-(methylsulfonyl)azetidin-3-yl)methyl, (1-acetylazetidin-3-yl)methyl,1-acetylpyrrolidin-3-yl, (tetrahydro-2H-pyran-4-yl)methyl,ethylcarbamoyl, cyclopropylcarbamoyl, (2-hydroxyethyl)carbamoyl,propylcarbamoyl, isopropylcarbamoyl, 1-cycanocyclopropyl, carbamoyl,morpholino, 1-cyanomethylpyrrolidin-1-yl, or pyridin-3-ylmethyl.

In some embodiments, the subscript n is 0, 1, or 2. In some embodiments,the subscript n is 0. In some embodiments, the subscript n is 1. Inanother embodiment, the subscript n is 2. In another embodiment, thesubscript n is 3.

In some embodiments:

Ring A is phenyl or a 6-membered heteroaryl ring;

R¹⁰ and R¹¹ are C₁₋₆ alkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group,which is optionally substituted with 1 or 2 independently selectedR^(10A) groups.

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1-3 independently selectedR^(b) substituents;

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R, NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c), andS(O)₂NR^(c)R^(c); and

each R^(c) is independently selected from H and C₁₋₆ alkyl; and

subscript n is 0, 1, 2, or 3.

In some embodiments:

X¹ is CR¹⁰R¹¹;

X² is CH;

Ring A is phenyl or a 6-membered heteroaryl ring;

R¹⁰ and R¹¹ are C₁₋₆ alkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group,which is optionally substituted with 1 or 2 independently selectedR^(10A) groups.

each R¹² is independently selected from halo, CN, NR^(a)R^(a),NR^(a)OR^(a), NHC(O)R^(a), NHS(O)₂R^(a), C(O)R^(a), S(O)₂R^(a), OR^(a),C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-6 membered heteroaryl, and 4 to 6-memberedheterocycloalkyl, wherein said C₁₋₆ alkyl, 5-6 membered heteroaryl, or 4to 6-membered heterocycloalkyl is optionally substituted with from 1-3R^(b);

each R^(b) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(i)R^(i), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c), and S(O)₂NR^(c)R^(c);

each R^(c) is independently selected from H and C₁₋₆ alkyl; and

subscript n is 0, 1, 2, or 3.

In some embodiments:

X¹ is CR¹⁰R¹¹;

X² is CH;

Ring A is phenyl or pyridyl;

R¹⁰ and R¹¹ are C₁₋₆ alkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group,which is optionally substituted with 1 or 2 independently selectedR^(10A) groups;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6membered heterocycloalkyl)-C₁₋₂ alkyl-, CN, OR^(a), C(O)R^(a),NR^(a)R^(a), NR^(a)S(O)₂R^(a), and S(O)₂R^(a);

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl; and

subscript n is 0, 1, 2, or 3.

In some embodiments, when ring A is a 5-6 membered heteroaryl ring, thenring A is connected by a carbon atom to the moiety below at the pointindicated by the wavy line:

Subformulas

In some embodiments, compounds of Formula (I′) or (I) have subformula(Ia):

or a pharmaceutically acceptable salt thereof, wherein the variablesring A, R¹, R², R³, R⁴, R⁵, R¹⁰, R¹¹, R¹², X² and n are as defined inany embodiment of compounds of Formula (I′) or (I).

In some embodiments of compounds of Formula (Ia):

ring A is a C₆₋₁₀ aryl or a 5 to 6-membered heteroaryl having carbon and1 to 4 heteroatoms as ring members selected from O, N and S;

each R¹² is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NR^(a)R^(a), NR^(a)OR^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c),NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c), and S(O)₂NR^(c)R^(c); or two adjacent R¹²substituents on ring A taken together with the atoms to which they areattached form a fused 5- or 6-member cycloalkyl ring, 5 to 6-memberedheterocycloalkyl ring, phenyl or 5 to 6-membered heteroaryl ring,wherein the heterocycloalkyl or heteroaryl have 1-2 heteroatoms as ringmembers selected from O, N and S;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e);

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 R^(f) substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NR^(g)R^(g), NR^(g)C(O)R, NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),and S(O)₂NR^(g)R^(g);

or any two R^(a) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(i), SR^(i), C(O)R^(i), C(O)NR^(i)R^(i),C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or3 R^(j) substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(i), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

or any two R^(c) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(e), R^(g), R^(i) or R^(k) is independently selected from H, C₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₄ alkenyl or C₂₋₄ alkynyl, isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

X² is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶ is H, halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁶ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A);

R¹⁰ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-10 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl groups of R¹⁰ are each optionally substituted with 1,2, 3, or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) are independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

R¹¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹⁹;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

each R^(a9), R^(c9), and R^(d9) is independently selected from H andC₁₋₄ alkyl;

each R^(b9) is independently C₁₋₄ alkyl; and

n as an integer is 0, 1, 2, or 3. In some embodiments, compounds ofFormula (Ia) have selective inhibitory activity on FGFR4 enzyme or anymutant thereof. In other embodiments, compounds of Formula (Ia) haveselective inhibitory activity on FGFR3 enzyme or any mutant thereof. Inother embodiments, compounds of Formula (Ia) have selective inhibitoryactivity on both FGFR3 and FGFR4 enzyme or any mutant thereof

In some embodiments, compounds of Formula (I′) or (I) have subformula(Ib):

or a pharmaceutically acceptable salt thereof, wherein the variablesring A, R¹, R², R³, R⁴, R⁵, R⁷, R¹², X² and n are as defined in anyembodiment of compounds of Formula (I′) or (I). In some embodiments, R⁷is H, halo, CN, or C₁₋₆ alkyl. In one embodiment, R⁷ is H or C₁₋₆ alkyl.

In some embodiments, compounds of Formula (I′) or (I) have subformula(Ic):

or a pharmaceutically acceptable salt thereof, wherein the variables R¹,R², R³, R⁴, R⁵, R¹⁰, R¹, R¹², X² and n are as defined in any embodimentof compounds of Formula (I′) or (I).

In some embodiments,

R² is F or Cl;

R⁵ is F or Cl;

R¹⁰ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-10 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl groups of R¹⁰ are each optionally substituted with 1,2, 3, or 4 R^(10A);

each R^(10A) is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R^(10a) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R^(a4), R^(b4), R^(c4), andR^(d4) are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁹; alternatively, R^(c4) and R^(d4)together with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group which is optionallysubstituted with 1, 2 or 3 substituents s independently selected fromR¹⁹;

R^(e4) is H or C₁₋₄ alkyl;

R¹¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, or 7-membered heterocycloalkyl group; wherein said 3-, 4-,5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, or 7-memberedheterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4R^(10A);

each R¹⁹ is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl; wherein C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl areeach further optionally substituted with 1 or 2 R²⁰ substituentsindependently selected from H, halo, CN, NO₂, OR^(q), SR^(q), C(O)R^(q),C(O)NR^(q)R^(q), C(O)OR^(q), OC(O)R^(q), OC(O)NR^(q)R^(q), NR^(q)R^(q),NR^(q)C(O)R^(q), NR^(q)C(O)OR^(q), NR^(q)C(O)NR^(q)R^(q),NR^(q)S(O)R^(q), NR^(q)S(O)₂R^(q), NR^(q)S(O)₂NR^(q)R^(q), S(O)R^(q),S(O)NR^(q)R^(q), S(O)₂R^(q), S(O)₂NR^(g)R^(q), C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₆cycloalkyl and C₁₋₄ haloalkyl, wherein each R^(q) isindependently H or C₁₋₄alkyl

each R^(a9), R^(c9), and R^(d9) are independently selected from H andC₁₋₄ alkyl; and

R^(b9) is C₁₋₄ alkyl.

In some embodiments, X² is N.

In some embodiments, X² is CR⁶.

In some embodiments, R⁶ is H, halo, CN, or C₁₋₆ alkyl. In someembodiments, R⁶ is H.

In some embodiments, R⁶ is C₁₋₆ alkyl. In some embodiments, R⁶ ismethyl. In some embodiments, R⁶ is halo. In some embodiments, R⁶ is CN.

In some embodiments, R¹ is C₁₋₃ alkyl. In some embodiments, R¹ ismethyl.

In some embodiments, R² is halo. In some embodiments, R² is fluoro. Insome embodiments, R² is chloro.

In some embodiments, R³ is H.

In some embodiments, R⁴ is C₁₋₃ alkyl. In some embodiments, R⁴ ismethyl.

In some embodiments, R⁵ is halo. In some embodiments, R⁵ is fluoro. Insome embodiments, R⁵ is chloro.

In some embodiments, R² is fluoro and R⁵ is fluoro. In some embodiments,R² is chloro and R⁵ is chloro.

In some embodiments, R¹ is C₁₋₃ alkyl; R² is halo; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is halo.

In some embodiments, R¹ is C₁₃ alkyl; R² is F; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is F.

In some embodiments, R¹ is methyl; R² is F; R³ is H; R⁴ is methyl; andR⁵ is F.

In some embodiments, R¹ is C₁₃ alkyl; R² is Cl; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is Cl.

In some embodiments, R¹ is methyl; R² is Cl; R³ is H; R⁴ is methyl; andR⁵ is Cl.

In some embodiments, R¹⁰ is C₁₋₆ alkyl. In some embodiments, R¹⁰ ismethyl.

In some embodiments, R¹¹ is C₁₋₆ alkyl. In some embodiments, R¹¹ ismethyl.

In some embodiments, R¹⁰ and R¹¹ are each C₁₋₆ alkyl. In someembodiments, R¹⁰ and R¹ are each methyl.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl group. Insome embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, or 5-membered cycloalkyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl group. In some embodiments, R¹⁰ andR¹¹ together with the carbon atom to which they are attached form acyclobutyl group. In some embodiments, R¹⁰ and R¹¹ together with thecarbon atom to which they are attached form a cyclopentyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form a cyclohexyl group. In some embodiments, R¹⁰ and R¹¹together with the carbon atom to which they are attached form acycloheptyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl group optionally substituted by 1or 2 R^(10A). In some embodiments, R¹⁰ and R¹¹ together with the carbonatom to which they are attached form a cyclobutyl group optionallysubstituted by 1 or 2 R^(10A). In some embodiments, R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a cyclopentyl groupoptionally substituted by 1 or 2 R^(10A). In some embodiments, R¹⁰ andR¹¹ together with the carbon atom to which they are attached form acyclohexyl group optionally substituted by 1 or 2 R^(10A).

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a tetrahydropyranyl group, a tetrahydrofuranylgroup, tetrahydrothiophene group, a pyrrolidinyl group, or a piperidinylgroup. In some embodiments, R¹⁰ and R¹¹ together with the carbon atom towhich they are attached form a tetrahydropyranyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form a tetrahydropyranyl group optionally substituted by 1 or 2R^(10A). In some embodiments, R¹⁰ and R¹¹ together with the carbon atomto which they are attached form a tetrahydrofuranyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form a tetrahydrofuranyl group optionally substituted byR^(10A). In some embodiments, R¹⁰ and R¹¹ together with the carbon atomto which they are attached form an azetidinyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form an azetidinyl group optionally substituted by R^(10A).

In some embodiments, compounds of Formula (I′), (I) or (Ia) have subFormula (Id):

or a pharmaceutically acceptable salt thereof, wherein X², R¹, R², R³,R⁴, R⁵, R¹⁰, R¹¹, R¹² and n are as defined in any embodiment of Formula(I′) or (I) as described herein.

In some embodiments, compounds of Formula (I′), (I) or (Ia) have subFormula (Ie):

or a pharmaceutically acceptable salt thereof, wherein ring A, R², R³,R⁵, R¹⁰, R¹¹, R¹², X² and n are as defined in any embodiment of Formula(I′) or (I) as described herein.

In some embodiments, compounds of Formula (I′), (I), (Ia) or (le) havesub Formula (If):

or a pharmaceutically acceptable salt thereof, wherein ring A, R³, R¹⁰,R¹¹, R¹², X² and n are as defined in any embodiment of compounds ofFormula (I′) or (I) as described herein.

In some embodiments, compounds of Formula (I′), (I), (le) or (If) havesub Formula (Ig):

or a pharmaceutically acceptable salt thereof, wherein ring A, R¹⁰, R¹¹,X, R¹² and n are as defined in any embodiment of compounds of Formula(I′) or (I) as described herein. In some embodiments of compounds ofFormula (Ie), X² is N. In other embodiments, X² is CH. In oneembodiment, ring A is phenyl. In another embodiment, ring A is5-membered heteroaryl selected from 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl,1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl,1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol-4-yl,1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl,1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl,1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl,3-furanyl, 2-thiophenyl or 3-thiophenyl. In other embodiments, ring A is2-pyridyl, 3-pyridyl or 4-pyridyl. In some embodiments of compounds ofFormula (Ie), each R¹² is independently selected from NH₂, CH₃, F, CN,1-piperidinyl, methylcarbamoyl, 1-piperazinyl or 4-morpholinyl. In oneembodiment, the subscript n is 0. In one embodiment, the subscript nis 1. In another embodiment, the subscript n is 2. In anotherembodiment, the subscript n is 3.

In some embodiments, compounds of Formula (I′) or (I) have sub Formula(Ih):

The variables X¹, ring A, R¹² and n are as defined in any embodiment ofcompounds of Formula (I′) or (I) as described herein. In certaininstances, X¹ is —CR¹⁰R¹¹— or —NR⁷—. In some instances, X¹ is —CR¹⁰R¹¹—,where R¹⁰ and R¹¹ taken together form a C₃₋₆ cycloalkyl ring. In oneembodiment, R¹⁰ and R¹¹ taken together form a cyclopropyl ring. In otherinstances, X¹ is —NR⁷—. In one embodiment, R⁷ is C₁₋₆ alkyl. In oneembodiment, R⁷ is ethyl. In some instances, ring A is phenyl or3-pyridyl. In one instance, ring A is 4-pyrazolyl.

In some embodiments, compounds of Formula (I′) have sub Formula (Ih):

The variables R¹³, R¹⁴, X¹, ring A, R¹² and n are as defined in anyembodiment of compounds of formula (I′) or (I) as described herein. Insome instances, R¹³ is —C(O)NHC₁₋₆ alkyl and R¹⁴ is OCH₃. In certaininstances, X¹ is —CR¹⁰R¹¹— or —NR⁷—. In some instances, X¹ is —CR¹⁰R¹¹—,where R¹⁰ and R¹¹ taken together form a C₃₋₆ cycloalkyl ring. In oneembodiment, R¹⁰ and R¹¹ taken together form a cyclopropyl ring. In otherinstances, X¹ is —NR⁷—.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Definitions

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkynyl groups include, but are not limited to,ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅,and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atomsor heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group. In some embodiments, the heterocycloalkyl groupis a morpholine ring, pyrrolidine ring, piperazine ring, piperidinering, dihydropyran ring, tetrahydropyran ring, tetrahyropyridine,azetidine ring, or tetrahydrofuran ring.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl or naphthyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or 3 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl group is a monocyclic orbicyclic group having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, sulfur and oxygen. Example heteroaryl groups include, butare not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl,azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms inthe ring(s) of the heteroaryl group can be oxidized to form a carbonyl,an N-oxide, or a sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized, provided the aromatic nature of thering is preserved. In one embodiment the heteroaryl group is a 5 to 10membered heteroaryl group. In another embodiment the heteroaryl group isa 5 to 6 membered heteroaryl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography—mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphorylchloride); RP-HPLC (reverse phase high performance liquidchromatography); s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR4 enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the FGFR4enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)preventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease; 2) inhibiting the disease;for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology), or 3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds as disclosed herein can be prepared by one skilled in the artaccording to preparatory routes known in the literature. Examplesynthetic methods for preparing compounds of the invention are providedin the Schemes below.

The synthesis of compound 4 is outlined in Scheme 1. Ester 1 can bereduced to the corresponding aldehyde 2 using DIBAL-H. The reductiveamination on this aldehyde with aniline 3 can afford dichloropyridine 4.

Dichloropyrimidine 8 can be prepared by the methods described in Scheme2. Treatment of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione with POCl₃can afford trichloride 6, which can be converted to iodide 7 using NaI.Compound 7 can be coupled with aniline 3, in the presence of a base suchas, iPr₂NEt, Cs₂CO₃, or NaH, to give dichloropyrimidine 8.

The synthesis of compound 13 is outlined in Scheme 3. Compound 9 can betreated with ethyl 3-chloro-3-oxopropanoate and NaH in THF to provideamide 10. Lactam 11 can be prepared by the treatment of compounds 10with a strong base, such as NaH or Cs₂CO₃ in DMF, and followed by anacid, such as HCl, mediated decarboxylation. α-Substituted lactam 12 canbe obtained by treating compound 11 with a base, such as NaH or Cs₂CO₃in DMF or acetonitrile, and followed by the addition of halides R¹⁰Xand/or R¹¹X (X is halo such as Cl, Br, or I). Chloride 12 can beconverted to compound 13, wherein M is a boronic acid, boronic ester oran appropriately substituted metal (e.g., M is B(OH)₂, Sn(Bu)₃, orZnBr), under standard Suzuki conditions {e.g., in the presence of apalladium catalyst, such as, but not limited to,[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) and abicarbonate or carbonate base}, or standard Stille conditions [e.g., inthe presence of a palladium catalyst, such as, but not limited to,Pd(dba)₂] or standard Negishi conditions [e.g., in the presence of apalladium catalyst, such as, but not limited to,tetrakis(triphenylphosphine)palladium(0)].

Compound 16 can be synthesized following the procedure shown in Scheme4. Therefore, compound 9 is first treated with triphosgene in thepresence of a base such as pyridine, and then with amine R⁷NH₂ in thepresence of another base (e.g. DIPEA) to afford urea compound 14. Upontreatment with a proper base (e.g. Cs₂CO₃), cyclization of 14 takesplace to generate cyclic urea 15, which can then be converted tocompound 16, wherein M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., M is B(OH)₂, Sn(Bu)₃, or ZnBr).The coupling reaction to yield 16 can occur under standard Suzukiconditions {e.g., in the presence of a palladium catalyst, such as, butnot limited to,[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) and abicarbonate or carbonate base}, or standard Stille conditions [e.g., inthe presence of a palladium catalyst, such as, but not limited to,Pd(dba)₂] or standard Negishi conditions [e.g., in the presence of apalladium catalyst, such as, but not limited to,tetrakis(triphenylphosphine)palladium(0)].

Compound 21 can be prepared according to the synthetic proceduresdescribed in Scheme 5. The reductive amination of aldehyde 18 withaniline 17 can afford compound 19. Compound 19 is treated withtriphosgene in the presence of a base such as triethylamine to affordurea 20.

Compound 20 can then be converted to compound 21, wherein M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., M isB(OH)₂, Sn(Bu)₃, or ZnBr). The coupling reaction to yield 21 can occurunder standard Suzuki conditions {e.g., in the presence of a palladiumcatalyst, such as, but not limited to,[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) and abicarbonate or carbonate base}, or standard Stille conditions [e.g., inthe presence of a palladium catalyst, such as, but not limited to,Pd(dba)₂] or standard Negishi conditions [e.g., in the presence of apalladium catalyst, such as, but not limited to,tetrakis(triphenylphosphine)palladium(0)].

Compound 21 can be synthesized using an alternative procedure shown inScheme 6. Ester 1 can be reduced to the corresponding aldehyde 2 usingDIBAL-H. The reductive amination of this aldehyde with aniline 17 canafford compound 22. Compound 22 is then converted to 23, wherein M is aboronic acid, boronic ester or an appropriately substituted metal (e.g.,M is B(OH)₂, Sn(Bu)₃, or ZnBr). The coupling reaction to yield 23 canoccur under standard Suzuki conditions {e.g., in the presence of apalladium catalyst, such as, but not limited to,[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) and abicarbonate or carbonate base}, or standard Stille conditions [e.g., inthe presence of a palladium catalyst, such as, but not limited to,Pd(dba)₂] or standard Negishi conditions [e.g., in the presence of apalladium catalyst, such as, but not limited to,tetrakis(triphenylphosphine)palladium(0)]. Compound 23 can undergoBuchwald coupling with amine R⁷NH₂ under standard conditions {e.g., inthe presence of a palladium catalyst, such as, but not limited to,(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladiumand a base, such as, but not limited to, cesium carbonate or sodiumtert-butoxide} then cyclized with triphosgene in the presence of a basesuch as triethylamine to provide compound 21.

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, the compounds of the disclosure can be used toselectively inhibit the activity of an FGFR3 and/or FGFR4 enzyme in acell or in an individual or patient in need of inhibition of the enzymeby administering an inhibiting amount of a compound of the disclosure tothe cell, individual, or patient.

In some embodiments, the compounds of the disclosure are selective forthe enzyme FGFR4 over one or more of FGFR1, FGFR2, and/or FGFR3. In someembodiments, the compounds of the disclosure have selective inhibitoryactivity for the FGFR4 enzyme over FGFR1, FGFR2, and FGFR3. In someembodiments, the compounds of the disclosure are selective for theenzyme FGFR4 over VEGFR2. In some embodiments, the selectivity is 2-foldor more, 3-fold or more, 5-fold or more, 10-fold or more, 25-fold ormore, 50-fold or more, or 100-fold or more.

In some embodiments, the compounds of the disclosure have selectiveinhibitory activity for the enzyme FGFR3 over one or more of FGFR1and/or FGFR2 and/or FGFR4. In some embodiments, the compounds of thedisclosure are selective for the enzyme FGFR3 over FGFR1 and FGFR2. Incertain embodiments, the compounds of the disclosure are selective forthe enzyme FGFR3 over FGFR1. In certain embodiments, the compounds ofthe disclosure are selective for the enzyme FGFR3 over FGFR4. In someembodiments, the compounds of the disclosure are selective for theenzyme FGFR3 over VEGFR2. In some embodiments, the selectivity of thecompounds of the present disclosure for FGFR3 over FGFR1 and/or FGFR2and/or FGFR4 is 2-fold or more, 3-fold or more, 5-fold or more, 10-foldor more, 25-fold or more, 50-fold or more, or 100-fold or more.

As selective FGFR3 and/or FGFR4 inhibitors, the compounds of thedisclosure are useful in the treatment of various diseases associatedwith abnormal expression or activity of the FGFR3 and/or FGFR4 enzyme orFGFR ligands. Compounds which inhibit FGFR will be useful in providing ameans of preventing the growth or inducing apoptosis in tumors,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumours withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors.

In certain embodiments, the FGFR4, or a mutant thereof, activity isinhibited irreversibly. In certain embodiments, FGFR4, or a mutantthereof, activity is inhibited irreversibly by covalently modifying Cys552 of FGFR4.

In certain embodiments, the disclosure provides a method for treating aFGFR4-mediated disorder in a patient in need thereof, comprising thestep of administering to said patient an effective amount of a compoundaccording to the invention, or a pharmaceutically acceptable compositionthereof.

As selective FGFR3 inhibitors, the compounds of the disclosure areuseful in the treatment of various diseases associated with abnormalexpression or activity of the FGFR3 enzyme or FGFR ligands.

In certain embodiments, the disclosure provides a method for treating aFGFR3-mediated disorder in a patient in need thereof, comprising thestep of administering to said patient an effective amount of a compoundaccording to the invention, or a pharmaceutically acceptable compositionthereof.

In certain embodiments, compounds of the disclosure are useful in thetreatment of cancer. Exemplary cancers include bladder cancer, breastcancer, cervical cancer, colorectal cancer, cancer of the smallintestine, colon cancer, rectal cancer, cancer of the anus, endometrialcancer, gastric cancer, head and neck cancer (e.g., cancers of thelarynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth), kidneycancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocellularcarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancerand non-small cell lung carcinomas, parvicellular and non-parvicellularcarcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonaryblastoma), ovarian cancer, prostate cancer, testicular cancer, uterinecancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g.exocrine pancreatic carcinoma), stomach cancer, thyroid cancer,parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposisarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma,medulloblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors).

Further example cancers include hematopoietic malignancies such asleukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma,adult T cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acutemyelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma,myeloproliferative neoplasms (e.g., polycythemia vera, essentialthrombocythemia, and primary myelofibrosis), Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma,acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt'slymphoma.

Other cancers treatable with the compounds of the disclosure includetumors of the eye, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma,and osteosarcoma. Compounds of the disclosure can also be useful in theinhibition of tumor metastisis.

In some embodiments, the present disclosure provides a method fortreating hepatocellular carcinoma in a patient in need thereof,comprising the step of administering to a patient a compound of Formula(I′) or (I) or a compound as disclosed herein, or a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula (I′) or (I) or a compound as disclosed herein.

In some embodiments, the present disclosure provides a method fortreating Rhabdomyosarcoma, esophageal cancer, breast cancer, or cancerof a head or neck, in a patient in need thereof, comprising the step ofadministering to the patient a compound Formula (I′) or (I) or acompound as disclosed herein, or a pharmaceutically acceptable saltthereof, or a composition comprising a compound of Formula (I′) or (I)or a compound as disclosed herein.

In some embodiments, the present disclosure provides a method oftreating cancer, wherein the cancer is selected from hepatocellularcancer, breast cancer, bladder cancer, colorectal cancer, melanoma,mesothelioma, lung cancer, prostate cancer, pancreatic cancer,testicular cancer, thyroid cancer, squamous cell carcinoma,glioblastoma, neuroblastoma, uterine cancer, and rhabdosarcoma.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder including, but not limiting to, achrondroplasia,hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinicalforms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndromes. The method includes administering to thepatient in need thereof an effective amount of a compound Formula (I′)or (I) or a compound as disclosed herein, or a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula (I′) or (I) or a compound as disclosed herein.

The compounds of the invention can also be useful in the treatment ofhypophosphatemia disorders including, for example, X-linkedhypophosphatemic rickets, autosomal recessive hypophosphatemic rickets,autosomal dominant hypophosphatemic rickets, and tumor-inducedosteromalacia. In some embodiments, the present disclosure provides amethod for treating a patient suffering from a hypophosphatemia disorderincluding, but not limiting to, X-linked hypophosphatemic rickets,autosomal recessive hypophosphatemic rickets, autosomal dominanthypophosphatemic rickets, and tumor-induced osteromalacia. The methodincludes administering to the patient in need thereof an effectiveamount of a compound Formula (I′) or (I) or a compound as disclosedherein, or a pharmaceutically acceptable salt thereof, or a compositioncomprising a compound of Formula (I′) or (I) or a compound as disclosedherein.

The compounds of the invention may further be useful in the treatment offibrotic diseases, such as where a disease symptom or disorder ischaracterized by fibrosis. Example fibrotic diseases include livercirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis,rheumatoid arthritis, and wound healing.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withthe compounds of Formula (I′) or (I) or a compound as described hereinfor treatment of FGFR-associated diseases, disorders or conditions. Theagents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with the compounds of the presentinvention for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this invention may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present invention. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists(e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) andagents that inhibit androgen production (e.g. abiraterone).

Compounds of the present invention may be combined with or in sequencewith other agents against membrane receptor kinases especially forpatients who have developed primary or acquired resistance to thetargeted therapy. These therapeutic agents include inhibitors orantibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 andagainst cancer-associated fusion protein kinases such as Bcr-Abl andEML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, andinhibitors against EGFR/Her2 include but are not limited to dacomitinib,afatinib, lapitinib and neratinib. Antibodies against the EGFR includebut are not limited to cetuximab, panitumumab and necitumumab.Inhibitors of c-Met may be used in combination with FGFR inhibitors.These include onartumzumab, tivantnib, and INC-280. Agents against Abl(or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib andthose against Alk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib.

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compounds ofthe present invention include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds of the present invention. In some embodiments,the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with the compounds of thepresent invention include chemotherapy combinations such asplatinum-based doublets used in lung cancer and other solid tumors(cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatinplus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin orcarboplatin plus pemetrexed) or gemcitabine plus paclitaxel boundparticles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with the compounds of thepresent invention include: dacarbazine (DTIC), optionally, along withother chemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds according to the invention may also be combinedwith immunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which refers toa combination of a compound of the invention, or its pharmaceuticallyacceptable salt, and at least one pharmaceutically acceptable carrier.These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

The compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the FGFR enzyme in tissuesamples, including human, and for identifying FGFR enzyme ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes FGFR enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention.

An “isotopically” or “radio-labeled” compound is a compound of theinvention where one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I,¹²⁵I and ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro FGFR enzyme labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, or ³⁵S will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the FGFR4 enzyme. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the FGFR4 enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more FGFR's as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 m particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 16′-(5-amino-2-methylphenyl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1: 4,6-dichloronicotinaldehyde

To a stirred solution of 2,4-dichloro-5-carbethoxypyridine (10.0 g, 45.4mmol) in methylene chloride (100.0 mL), diisobutylaluminum hydride inmethylene chloride (50.0 mL, 1.0 M, 50.0 mmol) was added dropwise at−78° C. After 2 hours, the reaction was quenched with a saturatedsolution of Rochelle's salt. After stirring for 12 hours, the aqueoussolution was extracted with DCM (3×150 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo to afford the crudealdehyde (7.51 g, 42.9 mmol), which was used directly in the next stepwithout further purification. LC-MS calculated for C₆H₄Cl₂NO [M+H]⁺ m/z:176.0; found 176.0.

Step 2:N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

To a stirred solution of 2,6-difluoro-3,5-dimethoxyaniline (9.03 g, 47.7mmol), sodium triacetoxyborohydride (38.0 g, 180 mmol) in methylenechloride (60 mL)/trifluoroacetic acid (30. mL),4,6-dichloronicotinaldehyde (8.00 g, 45.5 mmol) was added in smallportions at room temperature. After 1 hour, the volatiles were removedin vacuo and saturated aqueous NaHCO₃ (200 mL) was added. The resultingmixture was extracted with DCM (3×150 mL). The organic layers werecombined, dried over Na₂SO₄, and concentrated. The residue was purifiedon silica gel (eluting with 0 to 0-40% EtOAc in hexanes) to afford thedesired product (15.0 g). LC-MS calculated for C₁₄H₁₃Cl₂F₂N₂O₂[M+H]⁺m/z: 349.0; found 349.1.

Step 3: ethyl3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate

To a stirred solution ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(3.50 g, 10.0. mmol) in tetrahydrofuran (20 mL), NaH (60% w/w in mineraloil, 421 mg, 10.5 mmol) was added at room temperature. After 10 minutes,ethyl malonyl chloride (1.92 mL, 15.0 mmol) was added dropwise. Afteranother 1 hour, the reaction was quenched with saturated aqueous NH₄Cl,and extracted with DCM (3×100 mL). The organic layers were combined,dried over Na₂SO₄, and concentrated. The residue was purified on silicagel (eluting with 0 to 0-35% EtOAc in hexanes) to afford the desiredproduct (4.20 g, 9.1 mmol). LC-MS calculated for C₁₉H₁₉Cl₂F₂N₂O₅ [M+H]⁺m/z: 463.1; found 463.1.

Step 4: ethyl6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4-carboxylate

To a stirred solution of ethyl3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate(1.50 g, 3.24 mmol) in DMF (15. mL), NaH (60% w/w in mineral oil, 337mg, 8.42 mmol) was added at room temperature. The resulting mixture wasthen warmed up to 110° C. After 5 hours, the reaction was cooled to roomtemperature, and saturated aqueous NH₄Cl (50 mL) was added to formprecipitate. After filtration, the solid was dried in vacuo to givecrude cyclized product (0.95 g, 2.23 mmol). LC-MS calculated forC₁₉H₁₈ClF₂N₂O₅ [M+H]⁺ m/z: 427.1; found 427.0.

Step 5:6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-1,2-dihydro-2,7-naphthyridin-3(4H)-one

To a stirred solution of ethyl6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4-carboxylate(0.95 g, 2.23 mmol) in 1,4-dioxane (5 mL) hydrogen chloride (4.0 M indioxane, 2 mL, 8 mmol) was added at room temperature. The resultingmixture was warmed up to 100° C. After 4 hours, the reaction was cooledto ambient temperature, quenched with saturated aqueous NaHCO₃, andextracted with DCM (3×100 mL). The organic layers were combined, driedover Na₂SO₄, and concentrated. The residue was purified on silica gel(eluting with 0 to 0-30% EtOAc in DCM) to afford the desired product(0.75 g, 2.12 mmol). LC-MS calculated for C₁₆H₁₄ClF₂N₂O₃ [M+H]⁺ m/z:355.1; found 355.1.

Step 6:6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

To a stirred solution of6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-1,4-dihydro-2,7-naphthyridin-3(2H)-one(1.50 g, 4.23 mmol) in DMF (10 mL), cesium carbonate (3.03 g, 9.30 mmol)and 1-bromo-2-chloro-ethane (701 μL, 8.46 mmol) were added sequentiallyat room temperature. After 5 hours, the reaction was quenched withsaturated aqueous NH₄Cl, and extracted with DCM (3×75 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. The residuewas purified on silica gel (eluting with 0 to 0-50% EtOAc in hexanes) toafford the desired product (1.20 g, 3.15 mmol). LC-MS calculated forC₁₈H₁₆ClF₂N₂O₃ [M+H]⁺ m/z: 381.1; found 381.1.

Step 7:6′-(5-amino-2-methylphenyl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

A mixture of6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one(30.0 mg, 0.0788 mmol), (5-amino-2-methylphenyl)boronic acid (17.8 mg,0.118 mmol), sodium carbonate (18.4 mg, 0.173 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (3.0mg, 0.0039 mmol) in tert-butyl alcohol (3.0 mL)/water (3.0 mL) wasstirred and heated at 90° C. After 2 hours, the reaction mixture wasquenched with saturated aq. NH₄Cl, extracted with methylene chloride.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated to dryness under reduced pressure. The crude product waspurified on prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct (22 mg) as its TFA salt. LC-MS calculated for C₂₅H₂₄F₂N₃O₃[M+H]⁺ m/z: 452.2; found 452.2.

Example 26′-(5-amino-4-fluoro-2-methylphenyl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₅H₂₃F₃N₃O₃ [M+H]⁺ m/z: 470.2; Found: 470.2.

Example 34-amino-2-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)benzonitrile

This compound was prepared using procedures analogous to those forexample 1, step 7, with4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrilereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₅H₂₁F₂N₄O₃ [M+H]⁺ m/z: 463.2; Found: 463.2.

Example 46′-(5-aminopyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1:N-(5-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)pyridin-3-yl)acetamide

This compound was prepared using procedures analogous to those forexample 1, step 7, withN-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]acetamidereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₅H₂₃F₂N₄O₄ [M+H]⁺ m/z: 481.2; Found: 481.2.

Step 2:6′-(5-aminopyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

To a stirred solution ofN-{5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]pyridin-3-yl}acetamide(0.048 g, 0.10 mmol) in ethanol (3.0 mL), potassium hydroxide (2.0 M inwater, 0.15 mL, 0.30 mmol) was added at room temperature. The resultingmixture was heated at 60° C. overnight. The reaction was quenched withsaturated aqueous NH₄Cl and the volatiles were removed under reducedpressure. The residue was dissolved in methylene chloride and was washedwith saturated aq. NH₄Cl. The organic layer was dried over Na₂SO₄,filtered, and concentrated to dryness under reduced pressure. The crudeproduct was purified on prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product (26 mg) as its TFA salt LCMS calculated forC₂₃H₂₁F₂N₄O₃ (M+H)⁺ m/z: 439.2; Found: 439.2.

Example 52′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-fluoropyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with (5-fluoropyridin-3-yl)boronic acid replacing(5-amino-2-methylphenyl)boronic acid. LCMS calculated for C₂₃H₁₉F₃N₃O₃[M+H]⁺ m/z: 442.1; Found: 442.2.

Example 62′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-morpholinopyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]morpholinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₇H₂₇F₂N₄O₄ [M+H]⁺ m/z: 509.2; Found: 509.2.

Example 76′-(5-amino-2-methylpyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1:6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

A stirred mixture of 5-bromo-6-methylpyridin-3-amine (0.100 g, 0.535mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](0.136 g, 0.535 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (42 mg, 0.051 mmol), and potassium acetate(0.150 g, 1.53 mmol) in 1,4-dioxane (5.0 mL) was heated at 110° C. After2 hours, the reaction was quenched with saturated aqueous NH₄Cl, andextracted with DCM (3×30 mL). The organic layers were combined, driedover Na₂SO₄, and concentrated. The crude product was used directly inthe next step without further purification.

Step 2:6′-(5-amino-2-methylpyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-aminereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₄H₂₃F₂N₄O₃ [M+H]⁺ m/z: 453.2; Found: 453.2.

Example 85-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)nicotinonitrile

This compound was prepared using procedures analogous to those forexample 7, step 1 to 2, with 5-bromonicotinonitrile replacing5-bromo-6-methylpyridin-3-amine in step 1. LCMS calculated forC₂₄H₁₉F₂N₄O₃ [M+H]⁺ m/z: 449.1; Found: 449.1.

Example 92′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(pyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with pyridin-3-ylboronic acid replacing(5-amino-2-methylphenyl)boronic acid. LCMS calculated for C₂₃H₂₀F₂N₃O₃[M+H]⁺ m/z: 424.2; Found: 424.2.

Example 102′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-methoxypyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₄H₂₂F₂N₃O₃ [M+H]⁺ m/z: 454.2; Found: 454.1.

Example 116′-(5-chloropyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₃H₁₉ClF₂N₃O₃ [M+H]⁺ m/z: 458.1; Found: 458.1.

Example 126′-(5-(1H-imidazol-1-yl)pyridin-3-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with3-(1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₆H₂₂F₂N₅O₃ [M+H]⁺ m/z: 490.2; Found: 490.1.

Example 132′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-(morpholine-4-carbonyl)pyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, withmorpholino(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanonereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₈H₂₇F₂N₄O₅ [M+H]⁺ m/z: 537.2; Found: 537.2.

Example 142′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-(morpholinosulfonyl)pyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylsulfonyl)morpholinereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₇H₂₇F₂N₄O₆S [M+H]⁺ m/z: 573.2; Found: 573.2.

Example 15N-(5-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)pyridin-3-yl)methanesulfonamide

This compound was prepared using procedures analogous to those forexample 1, step 7, withN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamidereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₄H₂₃F₂N₄O₅S [M+H]⁺ m/z: 517.1; Found: 517.1.

Example 162′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-(morpholinomethyl)pyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1:5-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-ylnicotinaldehyde

This compound was prepared using procedures analogous to those forexample 1, step 7, withN5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehydereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₄H₂₀F₂N₃O₄ [M+H]⁺ m/z: 452.1; Found: 452.1.

Step 2:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(5-(morpholinomethyl)pyridin-3-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

To a stirred solution of5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]nicotinaldehyde(20 mg, 0.04 mmol) and morpholine (7.7 μL, 0.088 mmol) in methylenechloride (5.0 mL), acetic acid (0.198 mL, 3.49 mmol) was added at roomtemperature. After 15 minutes, sodium triacetoxyborohydride (18.7 mg,0.0884 mmol) was added. After another 1 hour, the volatiles were removedand the residue was purified on prep-HPLC (pH=2, acetonitrile/water+TFA)to give the desired product (10 mg) as its TFA salt. LCMS calculated forC₂₈H₂₉F₂N₄O₄(M+H)⁺ m/z: 523.2; Found: 523.2.

Example 172′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-phenyl-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with phenylboronic acid replacing(5-amino-2-methylphenyl)boronic acid. LCMS calculated for C₂₄H₂₁F₂N₂O₃[M+H]⁺ m/z: 423.2; Found: 423.1.

Example 185-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-N-methylpicolinamide

This compound was prepared using procedures analogous to those forexample 1, step 7, withN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamidereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₅H₂₃F₂N₄O₄ [M+H]⁺ m/z: 481.2; Found: 481.1.

Example 194-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-N-methylbenzamide

This compound was prepared using procedures analogous to those forexample 1, step 7, with 4-(methylcarbamoyl)phenylboronic acid replacing(5-amino-2-methylphenyl)boronic acid. LCMS calculated for C₂₆H₂₄F₂N₃O₄[M+H]⁺ m/z: 480.2; Found: 480.2.

Example 205-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)picolinonitrile

This compound was prepared using procedures analogous to those forexample 1, step 7, with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile replacing(5-amino-2-methylphenyl)boronic acid. LCMS calculated for C₂₄H₁₉F₂N₄O₃[M+H]⁺ m/z: 449.1; Found: 449.1.

Example 212′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(1,3-dimethyl-1H-pyrazol-4-yl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₃H₂₃F₂N₄O₃ [M+H]⁺ m/z: 441.2; Found: 441.2. ¹H NMR (500 MHz, dmso) δ8.36 (s, 1H), 8.22 (s, 1H), 7.06 (t, J 8.0 Hz, 1H), 7.03 (s, 1H), 4.92(s, 2H), 3.89 (s, 6H), 3.78 (s, 3H), 2.40 (s, 3H), 1.71-1.73 (m, 2H),1.55-1.57 (m, 2H).

Example 223-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-phenyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1:7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of triphosgene (344 mg, 1.16 mmol) in CH₂Cl₂ (12 mL, 190mmol) at 0° C. was first added pyridine (0.250 mL, 3.09 mmol). Themixture was then stirred at 0° C. for 10 minutes, and added a solutionof N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline (900 mg, 2.58 mmol) in CH₂Cl₂ (8.0 mL). The reaction mixture wasstirred at 0° C. for 1 hour, and added ethylamine in THF (2.0 M, 6.4 mL,13 mmol), followed by N,N-diisopropylethylamine (920 μL, 5.3 mmol). Theresulting mixture was then warmed to room temperature, stirredovernight, quenched with saturated NaHCO₃ (aq) solution, and extractedwith EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄and concentrated to give the crude intermediate which was used directlyin the next step.

The crude intermediate obtained from previous step was first dissolvedin DMF (20 mL), and added Cs₂CO₃ (1.70 g, 5.2 mmol). The reactionmixture was then stirred at 95° C. for 5 hours until completion, cooledto room temperature, quenched with water, and extracted with EtOAc (3×20mL). The combined organic layers were dried over Na₂SO₄, andconcentrated. The resulting material was purified via columnchromatography (25% to 55% EtOAc in hexanes) to give the product as aslightly yellow solid. LC-MS calculated for C₁₇H₁₇ClF₂N₃O₃ [M+H]⁺ m/z:384.1; found 384.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-phenyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

A mixture of7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(35.0 mg, 0.0912 mmol), sodium carbonate (19.3 mg, 0.18 mmol),phenylboronic acid (16.7 mg, 0.14 mmol), and Pd-127 (6.9 mg, 0.0091mmol) in tert-butyl alcohol (1.0 mL) and water (1.0 mL) was firstdegassed with nitrogen, and then stirred and heated at 90° C. for 3hours. The resulting mixture was cooled to room temperature, dilutedwith water, and extracted with EtOAc (3×1.5 mL). The combined organiclayers were dried over Na₂SO₄, and concentrated. The resulting materialwas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to affordthe product as a white solid (TFA salt). LC/MS calculated forC₂₃H₂₂F₂N₃O₃ [M+H]⁺ m/z: 426.2; found 426.1.

Example 233-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(pyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 22, step 2, with3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine replacingphenylboronic acid. LC/MS calculated for C₂₂H₂₁F₂N₄O₃ [M+H]⁺ m/z: 427.2;Found: 427.1.

Example 245-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-methylpicolinamide

This compound was prepared using procedures analogous to those forexample 21, step 2, withN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamidereplacing phenyl boronic acid. LC/MS calculated for C₂₄H₂₄F₂N₅O₄ [M+H]⁺m/z: 484.2; Found: 484.1.

Example 25(S)-1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)benzyl)pyrrolidine-3-carbonitrile

This compound was prepared using procedures analogous to those forexample 22, step 2, with(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine-3-carbonitrilereplacing phenyl boronic acid. LC/MS calculated for C₂₉H₃₀F₂N₅O₃ [M+H]⁺m/z: 534.2; Found: 534.2.

Example 262-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)-2-methylpropanenitrile

This compound was prepared using procedures analogous to those forexample 22, step 2, with2-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propanenitrilereplacing phenyl boronic acid. LC/MS calculated for C₂₆H₂₆F₂N₅O₃ [M+H]⁺m/z: 494.2; Found: 494.2.

Example 271-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forexample 22, step 2, with1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrilereplacing phenyl boronic acid. LC/MS calculated for C₂₇H₂₆F₂N₅O₃ [M+H]⁺m/z: 506.2; Found: 506.2. ¹H NMR (600 MHz, DMSO) δ 9.34-9.32 (m, 1H),8.55 (dd, J=8.2, 2.4 Hz, 1H), 8.46 (s, 1H), 7.78-7.74 (m, 1H), 7.70 (s,1H), 7.07 (t, J=8.1 Hz, 1H), 4.85 (s, 2H), 4.06 (q, J=6.8 Hz, 2H), 3.91(s, 6H), 2.87-2.80 (m, 2H), 2.79-2.73 (m, 2H), 2.35-2.26 (m, 1H),2.13-2.05 (m, 1H), 1.23 (t, J=7.0 Hz, 3H).

Example 283-(7-(6-(1-cyanocyclobutyl)pyridin-3-yl)-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-5-methoxy-N-methylbenzamide

Step 1: 3-bromo-2-fluoro-5-iodobenzoic acid

To a mixture of 3-bromo-2-fluorobenzoic acid (1.50 g, 6.85 mmol) insulfuric acid (5.0 mL) at 0° C. was added N-iodosuccinimide (1.62 g,7.19 mmol) portionwise. The resulting mixture was warmed to roomtemperature, and kept stirring for 3 hours. The reaction mixture wasthen quenched with cold water, and the precipitate was collected byfiltration, washed with cold water, and dried under vacuum to give theproduct as a white solid, which was used directly in the next step (2.36g, 91%). LC-MS calculated for C₇H₄BrFIO₂ [M+H]⁺ m/z: 344.8; found 344.7.

Step 2. 3-bromo-2-fluoro-5-hydroxybenzoic acid

A mixture of 3-bromo-2-fluoro-5-iodobenzoic acid (2.15 g, 6.23 mmol),copper(I) oxide (130 mg, 0.94 mmol), and NaOH (1.25 g, 31.2 mmol) inwater (20 mL) was stirred at 100° C. overnight. The reaction mixture wascooled to room temperature and filtered. The filtrate was acidified with2 M HCl (aq) to ˜pH 1, and extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, and concentrated to give the product as ayellow solid, which was used directly in the next step (1.41 g, 96%).LC-MS calculated for C₇H₅BrFO₃ [M+H]⁺ m/z: 234.9; found 234.9.

Step 3: methyl 3-bromo-2-fluoro-5-methoxybenzoate

To a solution of 3-bromo-2-fluoro-5-hydroxybenzoic acid (4.88 g, 20.8mmol) in N,N-dimethylformamide (20 mL) at room temperature was firstadded K₂CO₃ (8.60 g, 62.3 mmol), followed by MeI (2.84 mL, 45.6 mmol).The reaction mixture was stirred at 80° C. for 1 hour, cooled to roomtemperature, quenched with water, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude material was then purified using column chromatography (0% to 30%EtOAc in hexanes) to give the product as a yellow solid (4.87 g, 89%).LC-MS calculated for C₉H₉BrFO₃ [M+H]⁺ m/z: 263.0; found 263.0.

Step 4: 3-bromo-2-fluoro-5-methoxy-N-methylbenzamide

A mixture of methyl 3-bromo-2-fluoro-5-methoxybenzoate (200 mg, 0.76mmol) in methanol (7.5 mL)/water (2.5 mL) at room temperature was addedNaOH (152 mg, 3.80 mmol).

The reaction mixture was stirred at room temperature for 2 hours, and1.0 M HCl in water (4.56 mL, 4.56 mmol) was added. The resulting mixturewas extracted with EtOAc, and the combined organic layers were driedover Na₂SO₄, filtered and concentrated to give carboxylic acidintermediate, which was used directly in the next step.

The carboxylic acid obtained from previous step was dissolved in CH₂Cl₂(7.5 mL), and BOP reagent (404 mg, 0.912 mmol), 2.0 M Methylamine in THF(1.52 mL, 3.04 mmol), and Et₃N (0.424 mL, 3.04 mmol) were addedsequentially. The reaction mixture was stirred at room temperature for 3hours before it was quenched with water, and extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified using column chromatography (0%to 50% EtOAc in hexanes) to give the product as a white solid. LC-MScalculated for C₉H₁₀BrFNO₂ [M+H]⁺ m/z: 262.0; found 262.0.

Step 5: 3-amino-2-fluoro-5-methoxy-N-methylbenzamide

A mixture of 3-bromo-2-fluoro-5-methoxy-N-methylbenzamide (205 mg, 0.78mmol), benzophenone imine (157 μL, 0.94 mmol),(9,9-dimethyl-9H-xanthene-4, 5-diyl)bis(diphenylphosphine) (45 mg, 0.078mmol), tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039 mmol), andCs₂CO₃ (381 mg, 1.17 mmol) in 1,4-dioxane (3.0 mL) was purged withnitrogen, and stirred at 95° C. for 24 hours. The reaction mixture wascooled to room temperature, diluted with water, and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified using column chromatography (25%to 55% EtOAc in hexanes) to give the imine intermediate, which was useddirectly in the next step.

The imine intermediate obtained from previous step was dissolved in THF(3.0 mL), and 1.0 M HCl in water (1.0 mL, 1.0 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour, neutralizedwith saturated NaHCO₃ solution, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified using column chromatography (0% to 10% MeOH inCH₂Cl₂) to give the product as a yellow solid (132 mg, 85% over twosteps). LC-MS calculated for C₉H₁₂FN₂O₂[M+H]⁺ m/z: 199.1; found 199.1.

Step 6:3-({[6-chloro-4-(ethylamino)pyridin-3-yl]methyl}amino)-2-fluoro-5-methoxy-N-methylbenzamide

To a solution of 3-amino-2-fluoro-5-methoxy-N-methylbenzamide (132 mg,0.66 mmol) and 6-chloro-4-(ethylamino)nicotinaldehyde (147 mg, 0.80mmol) in CH₂Cl₂ (3.0 mL) at room temperature was first addedtrifluoroacetic acid (1.0 mL). The resulting mixture was stirred at roomtemperature for 15 minutes. NaBH(OAc)₃ (211 mg, 1.00 mmol) was added infour portions over a period of 2 hours. The reaction mixture was thenstirred at room temperature for additional 1 hour before it was quenchedwith saturated NaHCO₃ solution, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified using column chromatography (0% to 60% EtOAcin hexanes) to give the product as a yellow solid (171 mg, 70%). LC-MScalculated for C₁₇H₂₁ClFN₄O₂ [M+H]⁺ m/z: 367.1; found 367.1.

Step 7:3-(7-chloro-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-5-methoxy-N-methylbenzamide

To a solution of3-({[6-chloro-4-(ethylamino)pyridin-3-yl]methyl}amino)-2-fluoro-5-methoxy-N-methylbenzamide(131 mg, 0.36 mmol) in THF (5.0 mL) at room temperature was added Et₃N(200 μL, 1.4 mmol), followed by triphosgene (85 mg, 0.28 mmol) in THF(1.0 mL). The reaction mixture was stirred at room temperature for 2hours. 1.0 M NaOH in water (1.4 mL, 1.4 mmol) was then added and theresulting mixture was stirred for another hour before it was extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄, filteredand concentrated. The residue was purified on column chromatography(0-50% EtOAc in hexanes) to give the product as a colorless oil (137 mg,98%). LC-MS calculated for C₁₈H₁₉ClFN₄O₃ [M+H]⁺ m/z: 393.1; found 393.1.

Step 8:3-(7-(6-(1-cyanocyclobutyl)pyridin-3-yl)-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-5-methoxy-N-methylbenzamide

A mixture of3-(7-chloro-1-ethyl-2-oxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)-2-fluoro-5-methoxy-N-methylbenzamide(20 mg, 0.051 mmol),[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (7.7mg, 0.010 mmol), Na₂CO₃ (11 mg, 0.10 mmol), and1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclobutanecarbonitrile(22 mg, 0.076 mmol) in water (1.0 mL)/t-BuOH (1.0 mL) was purged withnitrogen, and stirred at 100° C. for 3 hours. The reaction mixture wascooled to room temperature, and extracted with EtOAc. The combinedorganic layers were concentrated, and purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a white solid (TFA salt).LC-MS calculated for C₂₈H₂₈FN₆O₃ [M+H]⁺ m/z: 515.2; found 515.2. ¹H NMR(400 MHz, DMSO) δ 9.34 (d, J=1.7 Hz, 1H), 8.56 (dd, J=8.3, 2.3 Hz, 1H),8.45 (s, 1H), 8.27 (s, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.67 (s, 1H), 7.26(dd, J=5.9, 3.2 Hz, 1H), 7.07 (dd, J=4.9, 3.3 Hz, 1H), 4.87 (s, 3H),4.05 (q, J=6.7 Hz, 2H), 3.79 (s, 3H), 2.89-2.66 (m, 6H), 2.35-2.21 (m,1H), 2.09 (ddd, J=20.4, 9.0, 5.4 Hz, 1H), 1.23 (t, J=6.9 Hz, 3H).

Example 291-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1:N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(1.58 g, 4.52 mmol),1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.00 g, 4.52 mmol), tetrakis(triphenylphosphine)palladium(0) (520 mg,0.45 mmol) and potassium carbonate (2.50 g, 18.1 mmol) in a vial weredissolved in a mixture of water (7.1 mL) and 1,4-dioxane (20 mL) Thereaction mixture was then stirred at 120° C. overnight. The reactionmixture was quenched with saturated sodium bicarbonate solution andextracted three times with ethyl acetate. The combined extracts weredried over sodium sulfate and concentrated. The residue was purified onsilica gel (50-100% ethyl acetate in hexanes) to afford the desiredproduct (1.55 g, 31.6 mmol). LC-MS calculated for C₁₉H₁₉ClF₂N₄O₂ [M+H]⁺m/z: 409.1, found 409.1.

Step 2:N-(cyclopropylmethyl)-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-amine

Conditions A:

A solution ofN-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(50.0 mg, 0.122 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(10 mg, 0.01 mmol), sodium tert-butoxide (21 mg, 0.22 mmol), andcyclopropyl methylamine (15.6 μL, 0.183 mmol) in 1,4-dioxane (700 μL)was heated at 90° C. for 2 hours. The reaction mixture was diluted withdichloromethane and filtered through a plug of Celite. The filtrate wasconcentrated and the residue used directly in the next step. LC-MScalculated for C₂₃H₂₈F₂N₅O₂ [M+H]⁺ m/z: 444.2, found 444.2.

Conditions B:

A solution ofN-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(50.0 mg, 0.122 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(10 mg, 0.01 mmol), cesium carbonate (71 mg, 0.366 mmol), andcyclopropylmethylamine (15.6 μL, 0.183 mmol) in tert-butanol (800 μL)was heated at 100° C. overnight. The reaction mixture was diluted withdichloromethane and filtered through a plug of Celite. The filtrate wasconcentrated and the residue used directly in the next step.

Step 3:1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

The crude residue from the previous step was dissolved intetrahydrofuran (1.5 mL). Triethylamine (68.2 μL, 0.489 mmol) was addedand the mixture cooled to 0° C. Triphosgene (36.3 mg, 0.122 mmol) wasadded in one portion and the reaction mixture stirred at roomtemperature for 1 hour, then quenched with 1 N NaOH and stirred anadditional 1 hour at room temperature. The mixture was diluted withwater and extracted with ethyl acetate three times.

The combined organics were dried over sodium sulfate and concentrated.The crude product was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product (22 mg) as its TFAsalt. LC-MS calculated for C₂₄H₂₆F₂N₅O₃ [M+H]⁺ m/z: 470.2, found 470.2.

Example 303-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-propyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with n-propyl aminereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₃H₂₆F₂N₅O₃ [M+H]⁺ m/z: 458.2; Found: 458.2.

Example 313-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-methylisoxazol-3-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(5-methylisoxazol-3-yl)methanamine replacing cyclopropylmethylamine instep 2. LCMS calculated for C₂₅H₂₅F₂N₆O₄ [M+H]⁺ m/z: 511.2; Found:511.1. ¹H NMR (500 MHz, DMSO) δ 8.36 (s, 1H), 8.17 (s, 1H), 7.26 (s,1H), 7.09 (t, J=8.2 Hz, 1H), 6.13 (m, 1H), 5.23 (s, 2H), 4.87 (s, 2H),3.90 (s, 6H), 3.82 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

Example 321-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with cyclopentylaminereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₅H₂₈F₂N₅O₃ [M+H]⁺ m/z: 484.2; Found: 484.2.

Example 333-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(tetrahydrofuran-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, withtetrahydrofuran-3-amine (HCl salt) replacing cyclopropylmethylamine instep 2. LCMS calculated for C₂₄H₂₆F₂N₅O₄ [M+H]⁺ m/z: 486.2; Found:486.2.

Example 343-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorobenzyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with 4-fluorobenzyl aminereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₇H₂₅F₃N₅O₃ [M+H]⁺ m/z: 524.2; Found: 524.1.

Example 353-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(3-methylisoxazol-5-yl)methanamine replacing cyclopropylmethylamine instep 2. LCMS calculated for C₂₅H₂₅F₂N₆O₄ [M+H]⁺ m/z: 511.2; Found:511.2.

Example 361-((5-cyclopropylisoxazol-3-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(5-cyclopropylisoxazol-3-yl)methanamine replacingcyclopropylmethylamine in step 2. LCMS calculated for C₂₇H₂₇F₂N₆O₄[M+H]⁺ m/z: 537.2; Found: 537.2.

Example 373-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with1-(tetrahydro-2H-pyran-4-yl)methanamine replacing cyclopropylmethylaminein step 2. LCMS calculated for C₂₆H₃₀F₂N₅O₄ [M+H]⁺ m/z: 514.2; Found:514.2.

Example 383-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(3,4-dihydro-2H-chromen-6-yl)methanamine replacingcyclopropylmethylamine in step 2. LCMS calculated for C₂₉H₂₈F₂N₅O₅[M+H]⁺ m/z: 564.2; Found: 564.2.

Example 393-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(1-ethyl-1H-pyrazol-4-yl)methanamine replacing cyclopropylmethylaminein step 2. LCMS calculated for C₂₆H₂₈F₂N₇O₃ [M+H]⁺ m/z: 524.2; Found:524.1. ¹H NMR (600 MHz, DMSO) δ 8.39 (s, 1H), 8.25 (s, 1H), 7.73 (s,1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.11 (t, J=8.2 Hz, 1H), 5.08 (s, 2H),4.90 (s, 2H), 4.08 (q, J=7.2 Hz, 2H), 3.93 (s, 6H), 3.86 (s, 3H), 2.29(s, 3H), 1.31 (t, J=7.3 Hz, 3H).

Example 403-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with 4-fluoro anilinereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₆H₂₃F₃N₅O₃ [M+H]⁺ m/z: 510.2; Found: 510.1. ¹H NMR (600 MHz, DMSO) δ8.43 (s, 1H), 8.04 (s, 1H), 7.55-7.49 (m, 2H), 7.46-7.40 (m, 2H), 7.09(t, J=8.1 Hz, 1H), 6.28 (s, 1H), 4.99 (s, 2H), 3.91 (s, 6H), 3.77 (s,3H), 2.11 (s, 3H).

Example 411-(1,3-benzothiazol-6-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1,3-benzothiazol-6-amine replacing cyclopropylmethylamine in step 2.LCMS calculated for C₂₇H₂₃F₂N₆O₃S [M+H]⁺ m/z: 549.1; Found: 549.1.

Example 423-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-5-oxopyrrolidin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with4-amino-1-methylpyrrolidin-2-one replacing cyclopropylmethylamine instep 2. LCMS calculated for C₂₅H₂₇F₂N₆O₄ [M+H]⁺ m/z: 513.2; Found:513.2.

Example 431-(1-acetylpiperidin-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1: tert-butyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with4-amino-1-methylpyrrolidin-2-one replacing cyclopropylmethylamine instep 2. LCMS calculated for C₃₀H₃₇F₂N₆O₅ [M+H]⁺ m/z: 599.3; Found:599.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(piperidin-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To the crude residue from step 1 was added methanol (1 mL) and 4.0 M HClin 1,4-dioxane (1 mL). The reaction mixture stirred at room temperaturefor 1 hour, then concentrated. The crude product was purified onprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product (24mg) as its bis-TFA salt. LCMS calculated for C₂₅H₂₉F₂N₆O₃ [M+H]⁺ m/z:499.2; Found: 499.2.

Step 3:1-(1-acetylpiperidin-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

The product from step 2 (9.8 mg, 0.0135 mmol) was dissolved in methylenechloride (200 μL) and pyridine (5.5 μL, 0.0675 mmol) was added, followedby acetyl chloride (2.9 μL, 0.0405 mmol). The mixture was stirred atroom temperature overnight, then purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product (5 mg) as its TFAsalt. LCMS calculated for C₂₇H₃₁F₂N₆O₄ [M+H]⁺ m/z: 541.2; Found: 541.2.

Example 444-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with 4-aminobenzonitrilereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₇H₂₃F₂N₆O₃ [M+H]⁺ m/z: 517.2; Found: 517.1. ¹H NMR (600 MHz, DMSO) δ8.45 (s, 1H), 8.09 (d, J=4.7 Hz, 2H), 8.03 (s, 1H), 7.72 (d, J=4.7 Hz,2H), 7.10 (t, J=8.2 Hz, 1H), 6.29 (s, 1H), 5.00 (s, 2H), 3.91 (s, 6H),3.77 (s, 3H), 2.14 (s, 3H).

Example 453-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-pyrimidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition A) and step 3, with 5-aminopyrimidinereplacing cyclopropylmethylamine in step 2. LCMS calculated forC₂₄H₂₂F₂N₇O₃ [M+H]⁺ m/z: 494.2; Found: 494.1. ¹H NMR (600 MHz, DMSO) δ9.32 (d, J=0.9 Hz, 1H), 9.09 (d, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.07 (s,1H), 7.85 (dd, J=5.3, 1.3 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 6.70 (s, 1H),4.98 (s, 2H), 3.91 (s, 6H), 3.76 (s, 3H), 2.24 (s, 3H).

Example 463-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(5-methyl-1,3,4-oxadiazol-2-yl)methanamine replacingcyclopropylmethylamine in step 2. LCMS calculated for C₂₄H₂₄F₂N₇O₄[M+H]⁺ m/z: 512.2; Found: 512.2. ¹H NMR (600 MHz, DMSO) δ 8.40 (s, 1H),8.19 (s, 1H), 7.38 (s, 1H), 7.10 (t, J=8.1 Hz, 1H), 5.45 (s, 2H), 4.89(s, 2H), 3.90 (s, 6H), 3.83 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H).

Example 473-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-methyl-1H-pyrazol-4-amine replacing cyclopropylmethylamine in step 2.LCMS calculated for C₂₄H₂₄F₂N₇O₃ [M+H]⁺ m/z: 496.2; Found: 496.2. ¹H NMR(600 MHz, DMSO) δ 8.46 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.61 (d,J=0.7 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 6.70 (s, 1H), 4.97 (s, 2H), 3.92(s, 3H), 3.92 (s, 6H), 3.81 (s, 3H), 2.22 (s, 3H).

Example 483-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 29, step 2 (Condition B) and step 3, with1-(1,5-dimethyl-1H-pyrazol-4-yl)methanamine replacingcyclopropylmethylamine in step 2. LCMS calculated for C₂₆H₂₈F₂N₇O₃[M+H]⁺ m/z: 524.2; Found: 524.2. ¹H NMR (600 MHz, DMSO) δ 8.37 (s, 1H),8.23 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.10 (t, J=8.2 Hz, 1H), 5.08(s, 2H), 4.86 (s, 2H), 3.92 (s, 6H), 3.85 (s, 3H), 3.68 (s, 3H), 2.28(s, 3H), 2.25 (s, 3H).

Example 493-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 22, step 2, with3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing phenylboronic acid. LCMS calculated for C₂₁H₂₁F₂N₅O₃ [M+H]⁺m/z: 430.2; Found: 430.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

A mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(170.0 mg, 0.3959 mmol), cesium carbonate (520.0 mg, 1.6 mmol), and2-(4-morpholine)ethyl bromide hydrochloride (164.0 mg, 0.712 mmol) inacetonitrile (5.0 mL) was stirred and heated at 90° C. for 12 hours. Theresulting mixture was cooled to room temperature, diluted with water,and extracted with EtOAc (3×15 mL). The combined organic layers weredried over Na₂SO₄, and concentrated. The resulting material was purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₇H₃₃F₂N₆O₄ [M+H]⁺m/z: 543.2; found 543.2. ¹H NMR (500 MHz, dmso) δ 8.42 (s, 1H), 8.36 (s,1H), 7.23 (s, 1H), 7.07 (t, J=8.2 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=6.6Hz, 2H), 3.99 (q, J=7.0 Hz, 2H), 3.89 (s, 6H), 3.64 (t, J=6.6 Hz, 2H),2.47 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). Note: the signals for the 8protons on the morpholine were very broad and hidden in the baseline.

Example 503-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 22, step 2, with3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing phenylboronic acid. LCMS calculated for C₂₁H₂₂F₂N₅O₃ [M+H]⁺m/z: 430.2; Found: 430.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

A mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(20.0 mg, 0.0466 mmol), cesium carbonate (61.3 mg, 0.1883 mmol), and3-(bromomethyl)pyridine hydrobromide (21.2 mg, 0.0838 mmol) inacetonitrile (0.6 mL) was stirred and heated at 90° C. for 12 hours. Theresulting mixture was cooled to room temperature, diluted with water,and extracted with EtOAc (3×2 mL). The combined organic layers weredried over Na₂SO₄, and concentrated. The resulting material was purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₇H₂₆F₂N₆O₃ [M+H]⁺m/z: 521.2; found 521.2.

Example 513-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forexample 22, step 2, with3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing phenylboronic acid. LCMS calculated for C₂₁H₂₂F₂N₅O₃ [M+H]⁺m/z: 430.2; Found: 430.2.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

A mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(20.0 mg, 0.0466 mmol), cesium carbonate (61.3 mg, 0.1883 mmol), and2-chloro-1-morpholinoethanone (13.7 mg, 0.0838 mmol) in acetonitrile(0.6 mL) was stirred and heated at 90° C. for 12 hours. The resultingmixture was cooled to room temperature, diluted with water, andextracted with EtOAc (3×2 mL). The combined organic layers were driedover Na₂SO₄, and concentrated. The resulting material was purified viapH 2 preparative LC/MS (MeCN/water with TFA) to afford the product as awhite solid (TFA salt). LC/MS calculated for C₂₇H₃₁F₂N₆O₅ [M+H]⁺ m/z:557.2; found 557.2.

Example 522′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₂H₂₁F₂N₄O₃ [M+H]⁺ m/z: 427.1; Found: 427.1.

Step 2:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

A mixture of2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one(17.0 mg, 0.0399 mmol), cesium carbonate (40.0 mg, 0.1 mmol), and2-(4-morpholine)ethyl bromide hydrochloride (23.0 mg, 0.1 mmol) inacetonitrile (0.5 mL) was stirred and heated at 90° C. for 12 hours. Theresulting mixture was cooled to room temperature, diluted with water,and extracted with EtOAc (3×2 mL). The combined organic layers weredried over Na₂SO₄, and concentrated. The resulting material was purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₈H₃₁F₂N₅O₄ [M+H]⁺m/z: 540.2; found 540.2. ¹H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.36 (s,1H), 7.14-6.98 (m, 2H), 4.94 (s, 2H), 4.49 (t, J=6.4 Hz, 2H), 3.89 (s,6H), 3.73-3.49 (m, 2H), 2.45 (s, 3H), 1.86-1.64 (m, 2H), 1.56 (q, J=3.9Hz, 2H).

Example 532′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(1-ethyl-1H-imidazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazolereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₃H₂₃F₂N₄O₃ [M+H]⁺ m/z: 441.2; Found: 441.2.

Example 542′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-[1-(1,1-dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazol-4-yl]-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

Step 1:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forexample 1, step 7, with3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated forC₂₂H₂₁F₂N₄O₃ [M+H]⁺ m/z: 427.1; Found: 427.1.

Step 2:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-[1-(1,1-dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazol-4-yl]-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

A mixture of2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(3-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one(20.0 mg, 0.0469 mmol), cesium carbonate (40.0 mg, 0.1 mmol), and3-Bromotetrahydrothiophene 1,1-dioxide (23.0 mg, 0.12 mmol) inacetonitrile (0.6 mL) was stirred and heated at 90° C. for 12 hours. Theresulting mixture was cooled to room temperature, diluted with water,and extracted with EtOAc (3×2 mL). The combined organic layers weredried over Na₂SO₄, and concentrated. The resulting material was purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₆H₂₇F₂N₄O₅S [M+H]⁺m/z: 545.2; found 545.2.

Example 552′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

Step 1: tert-butyl 3-(4-(4, 4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(19.4 mg, 0.10 mmol), cesium carbonate (49.0 mg, 0.15 mmol), andtert-butyl 3-iodoazetidine-1-carboxylate (31.0 mg, 0.11 mmol) inacetonitrile (0.5 mL) was stirred and heated at 90° C. for 12 hours. Theresulting mixture was cooled to room temperature, and the reaction wasquenched with saturated aqueous NH₄Cl, and extracted with DCM (3×2 mL).The organic layers were combined, dried over Na₂SO₄, and concentrated.The crude product was used directly in the next step without furtherpurification.

Step 2: tert-butyl3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 1, step 7, with tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylatereplacing (5-amino-2-methylphenyl)boronic acid. The crude product wasused directly in the next step without further purification.

Step 3:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

tert-Butyl3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylatewas dissolved in hydrogen chloride solution, 4.0 M in dioxane (1 mL),and the resulting mixture was stirred at room temperature for 1 hour.The crude reaction mixture was concentrated, and then dissolved in DCM(0.6 mL). After cooling to 0° C., triethylamine (0.023 mL, 0.16 mmol)and methanesulfonyl chloride (0.010 mL, 0.129 mmol) were added slowlyinto the reaction mixture. The resulting solution was stirred at roomtemperature for 1 hour. The reaction was quenched with aq. NaHCO₃, (2mL) and extracted with EtOAc (3×2 mL). The combined organic layers weredried over Na₂SO₄, and concentrated. The resulting material was purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₅H₂₆F₂N₄O₅S [M+H]⁺m/z: 545.2; found 545.2.

Example 562-(1-acetyl-3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Step 1: tert-butyl3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(19.4 mg, 0.10 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0313 mL,0.209 mmol), and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate(19.4 mg, 0.10 mmol) in acetonitrile (0.5 mL) was stirred at roomtemperature for 12 hours. The resulting mixture was quenched withsaturated aqueous NH₄Cl, and extracted with DCM (3×2 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. The crudeproduct was used directly in the next step without further purification.

Step 2: tert-butyl3-(cyanomethyl)-3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 1, step 7, with tert-butyl3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylatereplacing (5-amino-2-methylphenyl)boronic acid. The crude product wasused directly in the next step without further purification.

Step 3:2-(1-acetyl-3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

tert-Butyl3-(cyanomethyl)-3-(4-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylatewas dissolved in hydrogen chloride solution, 4.0 M in dioxane (1 mL),and the resulting mixture was stirred at room temperature for 1 hour.The crude reaction mixture was concentrated, and then dissolved in DCM(0.6 mL). After cooling to 0° C., triethylamine (0.015 mL, 0.11 mmol)and acetyl chloride (0.010 mL, 0.140 mmol) were added slowly into thereaction mixture. The resulting solution was stirred at room temperaturefor 1 hour. The reaction was quenched with aq. NaHCO₃, (2 mL) andextracted with EtOAc (3×2 mL). The combined organic layers were driedover Na₂SO₄, and concentrated. The resulting material was purified viapH 2 preparative LC/MS (MeCN/water with TFA) to afford the product as awhite solid (TFA salt). LC/MS calculated for C₂₈H₂₇F₂N₆O₄ [M+H]⁺ m/z:549.2; found 549.2.

Table 5. The compounds in Table 5 were prepared in an analogous fashionto Example 29 using the appropriate amine building block and usingmethod A or B in Step 2 as noted below.

TABLE 5 LCMS Example Method Name/¹H NMR Structure (M + H)⁺  57 B3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridazin-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one: ¹H NMR (600 MHz, DMSO) δ 9.48(dd, J = 5.5, 1.1 Hz, 1H), 9.42 (dd, J = 2.6, 1.1 Hz, 1H), 8.46 (s, 1H),8.06 (s, 1H), 7.99 (dd, J = 5.6, 2.6 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H),6.47 (s, 1H), 4.99 (s, 2H), 3.90 (s, 6H), 3.73 (s, 3H), 2.20 (s, 3H).

494.2  58 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((2-methoxypyridin-4- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

537.2  59 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((6-methoxypyridin-3- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one: ¹H NMR (600 MHz, DMSO) δ 8.37(s, 1H), 8.21- 8.16 (m, 2H), 7.65 (dd, J = 8.6, 2.5 Hz, 1H), 7.16-7.07(m, 2H), 6.84 (d, J = 8.9 Hz, 1H), 5.23 (s, 2H), 4.93 (s, 2H), 3.92 (s,6H), 3.82 (s, 3H), 3.81 (s, 3H), 2.17 (s, 3H).

537.2  60 A 3-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)- yl)benzonitrile

517.2  61 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrimidin-5-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

494.2  62 B 4-((3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)- N-methylbenzamide

563.2  63 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (isoquinolin-7-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

543.2  64 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((5-ethylisoxazol-3-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

525.2  65 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrimidin-4-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2  66 A 5-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-2- fluorobenzonitrile

535.2  67 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

526.2  68 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((2-methylpyridin-4-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

521.2  69 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridin-4-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one: ¹H NMR (600 MHz, DMSO) δ 8.74(d, J = 6.4 Hz, 2H), 8.39 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 6.0 Hz,2H), 7.09 (t, J = 8.1 Hz, 1H), 6.96 (s, 1H), 5.43 (s, 2H), 4.96 (s, 2H),3.91 (s, 6H), 3.78 (s, 3H), 2.14 (s, 3H).

507.2  70 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrazin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

494.2  71 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1- (methylsulfonyl)piperidin-4-yl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

577.2  72 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((1-methyl-1H-pyrazol-4- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

510.2  73 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3,4-difluorobenzyl)-7-(1,3-dimethyl- 1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

542.2  74 B 5-((3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)- yl)methyl)picolinonitrile

532.2  75 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2- methylbenzo[d]oxazol-6-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

547.2  76 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

430.2  77 A 1-(4-(1H-pyrazol-1-yl)phenyl)- 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3- dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

558.2  78 A 3-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-5- fluorobenzonitrile

535.2  79 B 6-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)- yl)nicotinonitrile

518.2  80 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (oxazol-5-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

497.2  81 A 4-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-2- methoxybenzonitrile

547.2  82 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((5-methyloxazol-2-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

511.2  83 A 1-cyclopropyl-3-(2,6-difluoro- 3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

456.2  84 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrimidin-5-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2  85 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrazin-2-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2  86 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

493.2  87 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(6- methylpyrazin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2  88 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridazin-3-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2  89 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3- (1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

573.2  90 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- isopropyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

458.2  91 B 1-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)- yl)cyclopropanecarbonitrile

481.2  92 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

493.2  93 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((5-isopropylisoxazol-3- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

539.2  94 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyridin-2-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

507.2  95 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((2-methylthiazol-4-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

527.2  96 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((1-methyl-5-oxopyrrolidin-3-yl)methyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

527.2  97 A 2-(4-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)- yl)phenyl)acetonitrile

531.2  98 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4- (methylsulfonyl)phenyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

570.2  99 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3- fluorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

510.2 100 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1- methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

496.2 101 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

524.2 102 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3,4-difluorophenyl)-7-(1,3-dimethyl- 1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

528.2 103 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3,5-difluorophenyl)-7-(1,3-dimethyl- 1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

528.2 104 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4- methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

522.2 105 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- (pyrimidin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

494.2 106 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5- ethylpyrazin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

522.2 107 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5- methylpyrazin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

508.2 108 A (R)-3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

500.2 109 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3- methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

522.2 110 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2- fluorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

510.2 111 A 3-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N- methylbenzenesulfonamide

585.2 112 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5- methoxypyrazin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

524.2 113 A 4-(3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2- oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N,N- dimethylbenzamide

563.2 114 A 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2- (1-methyl-1H-pyrazol-4-yl)ethyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

524.2 115 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4- (5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

574.2 116 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((2-ethoxypyridin-4-yl)methyl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

551.2 117 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one

537.2 118 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((1-methyl-1H- benzo[d][1,2,3]triazol-5-yl)methyl)-3,4- dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

561.2 119 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2- oxoindolin-5-yl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

547.2 120 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2- methyl-3-oxoisoindolin-5-yl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one

561.2 121 B 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1- ((2-methylpyrimidin-4- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin- 2(1H)-one

522.2

Example 122 Methyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

Step 1. Preparation of tert-butyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 29, Step 2 (Condition B) and Step 3, with tert-butyl4-aminopiperidine-1-carboxylate replacing 4-aminomethyl pyridine in Step2. LCMS calculated for C₃₀H₃₇F₂N₆O₅ [M+H]⁺ m/z: 599.1; Found: 599.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(piperidin-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To the crude residue from Step 1 above was added methanol (1 mL) and 4.0M HCl 1,4-dioxane (1 mL) and the reaction mixture stirred at roomtemperature for 1 h, then concentrated. The crude product was purifiedon prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product(24 mg) as its bis-TFA salt. LCMS calculated for C₂₅H₂₉F₂N₆O₃ [M+H]⁺m/z: 499.2; Found: 499.1.

Step 3. Preparation of methyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-piperidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(7.00 mg, 0.0140 mmol) in tetrahydrofuran (500 μL) was addedN,N-diisopropylethylamine (9.78 μL, 0.0562 mmol) and methylchloroformate (1.63 μL, 0.0211 mmol). The reaction mixture was stirredovernight then diluted with methanol and purified directly by reversephase HPLC (pH=2, acetonitrile/water+TFA) to provide the desired productas the corresponding TFA salt. LCMS calculated for C₂₇H₃₁F₂N₆O₅ [M+H]⁺m/z: 557.2, found 557.2.

Example 123 Methyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate

Step 1. tert-butyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate

This compound was prepared using procedures analogous to those forExample 29, Step 2 (Condition B) and Step 3, with tert-butyl4-aminophenylcarbamate replacing 4-aminomethyl pyridine in Step 2. LCMScalculated for C₃₁H₃₃F₂N₆O₅ [M+H]⁺ m/z: 607.2; Found: 607.2.

Step 2. Preparation of1-(4-aminophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To the crude residue from Step 1 above was added methanol (1 mL) and 4.0M HCl 1,4-dioxane (1 mL) and the reaction mixture stirred at roomtemperature for 1 h, then concentrated. The crude product was purifiedby column chromatography (0-10% methanol in dichloromethane). LCMScalculated for C₂₆H₂₅F₂N₆O₃ [M+H]⁺ m/z: 507.2; Found: 507.2.

Step 3. Preparation of methyl4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate

To a solution of1-(4-aminophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(7.00 mg, 0.0140 mmol) in tetrahydrofuran (500 μL) was addedN,N-diisopropylethylamine (9.78 μL, 0.0562 mmol) and methylchloroformate (1.63 μL, 0.0211 mmol). The reaction mixture was stirredovernight, then diluted with methanol and purified directly by reversephase HPLC (pH=2, acetonitrile/water+TFA) to provide the desired productas the corresponding TFA salt. LC-MS calculated for C₂₈H₂₇F₂N₆O₅ [M+H]⁺m/z: 565.2, found 565.2.

Example 1241-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1. Preparation of(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanamine

To a solution of ethyl1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxylate (500 mg,2 mmol) in tetrahydrofuran (2 mL) was added 2.0 M lithiumtetrahydroaluminate in tetrahydrofuran (1.11 mL, 2.22 mmol) and themixture stirred at room temperature for 2 h, then quenched by theaddition of 20 μL water, 20 μL of a 15% aqueous NaOH solution, then anadditional 60 μL of water. After stirring an additional 1 h, thereaction mixture was filtered through a plug of Celite and concentrated.

To the above residue in methylene chloride (10 mL) was addedtriethylamine (644 μL, 4.62 mmol) and the mixture cooled to 0 degrees.Methanesulfonyl chloride (143 μL, 1.85 mmol) was added dropwise and themixture stirred at room temperature 30 min, then recooled to 0 degreesand quenched by the careful addition of 2 mL of water. The mixture waswashed with brine and the aqueous layer extracted with additionalmethylene chloride. The combined organics were dried over sodium sulfateand concentrated.

The residue was dissolved in N,N-dimethylformamide (10 mL) and sodiumazide (180 mg, 2.77 mmol) was added. The mixture was stirred overnightat room temperature, then quenched at 0 degrees by the addition of 1.5mL of water. The mixture was diluted with diethyl ether and the layersseparated. The organic layer was then washed with water and brine, thendried over sodium sulfate and concentrated.

The residue was dissolved in 1,4-Dioxane (1.5 mL) and resin boundtriphenylphosphine (924 mg, 2.77 mmol) was added. The mixture wasstirred for 1 h, then a 4:1 mixture of dioxane:water (1.5 mL total) wasadded and the mixture was stirred at room temperature overnight. Theresin was removed by filtration and the filtrate concentrated to yieldthe desired compound, which was used without further purification in thenext step. LC-MS calculated for C₁₀H₂₂N₃OSi [M+H]⁺ m/z: 228.2, found228.2.

Step 2. Preparation of1-((1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To a mixture ofN-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(50 mg, 0.1 mmol),1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)methanamine(41.7 mg, 0.183 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(9.5 mg, 0.012 mmol) and cesium carbonate (120 mg, 0.367 mmol) was addedtert-butyl alcohol (2 mL) and the reaction vessel evacuated and backfilled with nitrogen three times. The mixture was then stirred at 100degrees overnight, at which point LCMS showed complete conversion. Thereaction mixture was diluted with dichloromethane and filtered through apad of Celite. The filtrate was concentrated.

The residue was dissolved in tetrahydrofuran (2.2 mL) and triethylamine(68.2 μL, 0.489 mmol) was added. After cooling to 0 degrees, triphosgene(36.3 mg, 0.122 mmol) was added in one portion and the reaction mixtureallowed to stir at room temperature for 1 h, then quenched by theaddition of 1N NaOH and stirred for an additional 1 h. The mixture wasthen extracted with ethyl acetate and the organic layer dried oversodium sulfate and concentrated.

The residue was dissolved in trifluoroacetic acid (1.0 mL) and stirredat room temperature for 1 h. LCMS analysis showed complete conversion tothe desired product. The mixture was concentrated, then purified bycolumn chromatography (50-100% ethyl acetate in hexanes) to provide thedesired product as a brown powder. LC-MS calculated for C₂₄H₂₄F₂N₇O₃[M+H]⁺ m/z: 496.2, found 496.2.

Step 3. Preparation of1-((1-cyclopropyl-H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-on

A mixture of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(10 mg, 0.02 mmol), cyclopropylboronic acid (6.93 mg, 0.0807 mmol),sodium carbonate (8.56 mg, 0.0807 mmol), copper(II) diacetate (7.33 mg,0.0404 mmol) and 2,2′-bipyridine (6.30 mg, 0.0404 mmol) was dissolved in1,2-dichloroethane (200 μL) and the mixture was heated at 95 degreesovernight. The mixture was diluted with methanol and purified directlyby reverse phase HPLC (pH=2, acetonitrile/water+TFA) to provide thedesired product as a white solid. LC-MS calculated for C₂₇H₂₈F₂N₇O₃[M+H]⁺ m/z: 536.2, found 536.2.

Example 1252-(4-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)-1H-pyrazol-1-yl)acetonitrile

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(Example 124, Step 2; 17 mg, 0.034 mmol) in N,N-dimethylformamide (500μL) at 0 degrees was added sodium hydride (4.12 mg, 0.172 mmol) and themixture stirred at 0 degrees for 10 minutes. Bromoacetonitrile (23.9 μL,0.343 mmol) was then added and the reaction mixture stirred for 1 h atroom temperature. The reaction mixture was then diluted with methanoland purified directly by reverse phase HPLC (pH=2,acetonitrile/water+TFA) to provide the desired product as thecorresponding TFA salt. LC-MS calculated for C₂₆H₂₅F₂N₈O₃ [M+H]⁺ m/z:535.2, found 535.2.

Example 1261-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 125, with cyclopropylmethyl bromide replacing bromoacetonitrile.LCMS calculated for C₂₈H₃₀F₂N₇O₃ [M+H]⁺ m/z: 550.2; Found: 550.2.

Example 1273-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 125, with 2-(bromomethyl)tetrahydrofuran replacingbromoacetonitrile. LCMS calculated for C₂₉H₃₂F₂N₇O₄ [M+H]⁺ m/z: 580.2;Found: 580.2.

Example 1283-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 125, with 2-bromo-1,1-difluoroethane replacingbromoacetonitrile. LCMS calculated for C₂₆H₂₆F₄N₇O₃ [M+H]⁺ m/z: 560.2;Found: 560.2.

Example 1293-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1. Preparation of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine

To a 0 degree solution of 4-nitro-1H-pyrazole (250 mg, 2.2 mmol) intetrahydrofuran (10 mL) was added sodium hydride (60 wt % in mineraloil, 63.7 mg, 2.65 mmol) and the reaction mixture stirred for 10 minutesat this temperature. [β-(Trimethylsilyl)ethoxy]methyl chloride (430 μL,2.43 mmol) was then added dropwise and the reaction mixture stirred foran additional 1 h at room temperature. The reaction mixture was quenchedwith brine and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated. The residue was purified by columnchromatography (10-80% ethyl acetate in hexanes) to provide theintermediate protected nitro pyrazole.

The residue was dissolved in ethyl acetate (2.5 mL) and 10% palladium oncarbon (240 mg, 0.11 mmol) was added. The reaction vessel was evacuatedand backfilled with hydrogen gas (1 atm) and the reaction mixturestirred for 2 h at room temperature. The mixture was filtered through apad of Celite and concentrated. The residue was used without furtherpurification in the next step. LCMS calculated for C₉H₂₀N₃OSi [M+H]⁺m/z: 214.1; Found: 214.2.

Step 2. Preparation of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To a mixture ofN-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline(50 mg, 0.1 mmol),1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-amine (39.1 mg, 0.183mmol), RuPhos Pd G2 (9.5 mg, 0.012 mmol) and cesium carbonate (120 mg,0.367 mmol) was added tert-butyl alcohol (2 mL) and the reaction vesselevacuated and back filled with nitrogen three times. The mixture wasthen stirred at 100 degrees overnight. The reaction mixture was dilutedwith dichloromethane and filtered through a pad of Celite. The filtratewas concentrated.

The residue was dissolved in tetrahydrofuran (2.2 mL) and triethylamine(68.2 μL, 0.489 mmol) was added. After cooling to 0 degrees, triphosgene(36.3 mg, 0.122 mmol) was added in one portion and the reaction mixtureallowed to stir at room temperature for 1 h, then quenched by theaddition of 1N NaOH and stirred for an additional 1 h. The mixture wasthen extracted with ethyl acetate and the organic layer dried oversodium sulfate and concentrated. The residue was purified by columnchromatography (0-15% methanol in dichloromethane) to provide thedesired product as a light brown solid. This solid was further purifiedby reverse phase HPLC (pH=2, acetonitrile/water+TFA) to provide thedesired product as the corresponding TFA salt. LCMS calculated forC₂₃H₂₂F₂N₇O₃ [M+H]⁺ m/z: 482.2; Found: 482.2.

Example 1301-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 124, Step 3 with the product of Example 129 serving as thestarting material. LCMS calculated for C₂₆H₂₆F₂N₇O₃ [M+H]⁺ m/z: 522.2;Found: 522.2.

Example 1313-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-ethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 125 with3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(Example 129) replacing 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-oneand ethyl iodide replacing bromoacetonitrile. LCMS calculated forC₂₅H₂₆F₂N₇O₃ [M+H]⁺ m/z: 510.2; Found: 510.2.

Example 1323-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-propyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 131 with propyl iodide replacing ethyl iodide. LCMS calculatedfor C₂₆H₂₈F₂N₇O₃ [M+H]⁺ m/z: 524.2; Found: 524.2.

Example 1333-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-6-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1. Preparation of1-((2-(trimethylsilyl)ethoxy)methy)-1H-indazol-6-amine

To a solution of 5-nitroindazole (250 mg, 1.5 mmol) in tetrahydrofuran(10 mL) at 0 degrees was added sodium hydride (60% suspension in mineraloil, 67 mg, 1.7 mmol) and the mixture stirred for 10 minutes at 0degrees. [β-(Trimethylsilyl)ethoxy]methyl chloride (320 μL, 1.8 mmol)was then added dropwise and the reaction mixture warmed to roomtemperature and stirred for 1 h, at which point LCMS confirmed completeconversion. The reaction mixture was quenched with water and dilutedwith ethyl acetate. The layers were separated and the aqueous layerextracted with additional ethyl acetate. The combined organics weredried over sodium sulfate and concentrated. The residue was purified bycolumn (0-35% ethyl acetate in hexanes) to provide the desiredintermediate.

The residue from above was dissolved in ethyl acetate (10 mL) and 10%palladium on carbon (0.16 g, 0.15 mmol) was added. The reaction was thenplaced under balloon pressure of hydrogen and stirred overnight thenfiltered and concentrated to provide the desired product, which waspurified by column chromatography (0-20% methanol in dichloromethane).LCMS calculated for C₁₃H₂₂N₃OSi [M+H]⁺ m/z: 264.2; Found: 264.2.

Step 2. Preparation of3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-6-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 29, Step 2 (Condition B) and Step 3, with the product from Step1 replacing cyclopropylmethylamine in Step 2. LCMS calculated forC₂₇H₂₄F₂N₇O₃ [M+H]⁺ m/z: 532.2; Found: 532.2.

Example 1343-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-5-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 133 with 4-nitroimidazole replacing 5-nitroimidazole. LCMScalculated for C₂₇H₂₄F₂N₇O₃ [M+H]⁺ m/z: 532.2; Found: 532.2.

Example 1351-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyrimidin-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

Step 1. Preparation of1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile

A mixture of 1-(6-bromopyridin-3-yl)cyclobutanecarbonitrile (500 mg, 2mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](802 mg, 3.16 mmol), potassium acetate (621 mg, 6.33 mmol), and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (92 mg,0.13 mmol) in 1,4-dioxane (8 mL) was first purged with nitrogen gas, andthen stirred at 90° C. overnight. The reaction mixture was then cooledto room temperature, diluted with ethyl acetate, filtered through a padof celite, and concentrated. The crude material was then purified viacolumn chromatography (0% to 30% EtOAc in hexanes) to give the productas a yellow solid. LCMS calculated for C₁₀H₁₂BN₂O₂[M+H for boronicacid]⁺ m/z: 203.1; Found: 203.1.

Step 2. Preparation of1-(4-chloro-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2,3′-bipyridin-6′-yl)cyclobutanecarbonitrile

A mixture ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(400 mg, 1 mmol),1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclobutanecarbonitrile(330 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (120 mg,0.10 mmol) and potassium carbonate (580 mg, 4.2 mmol) was dissolved in amixture of 1,4-dioxane (5 mL) and water (1 mL). The reaction flask wasevacuated and back filled with nitrogen, then heated to 120 degrees for2 h, at which point LCMS showed nearly complete conversion. The reactionmixture was quenched with saturated aqueous sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. The residue was purified by columnchromatography (0-30% ethyl acetate in hexanes) to provide the desiredproduct as a pale yellow solid. LCMS calculated for C₂₄H₂₂ClF₂N₄O₂[M+H]⁺ m/z: 471.1; Found: 471.1.

Step 3. Preparation of1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyrimidin-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

A mixture of1-(4-chloro-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-2,3′-bipyridin-6′-yl)cyclobutanecarbonitrile(30.0 mg, 0.0637 mmol), pyrimidin-4-amine (9.09 mg, 0.0956 mmol), RuPhosPd G2 (4.9 mg, 0.0064 mmol) and cesium carbonate (62.3 mg, 0.191 mmol)was dissolved in tert-butyl alcohol (0.6 mL) and the reaction flask wasevacuated and backfilled with nitrogen three times. The reaction wasthen stirred at 95 degrees overnight. The reaction was quenched by theaddition of saturated aqueous sodium bicarbonate, then diluted withethyl acetate. The layers were separated and the aqueous layer extractedwith additional ethyl acetate. The combined organics were dried oversodium sulfate and concentrated.

The residue was dissolved in tetrahydrofuran (0.75 mL) and triethylamine(25.8 mg, 0.255 mmol) was added. After cooling to 0 degrees, triphosgene(18.9 mg, 0.0637 mmol) was added and the mixture stirred at roomtemperature for 1 h, then diluted with methanol and purified usingreverse phase HPLC (pH=2, acetonitrile/water+TFA) to provide the desiredproduct as the corresponding TFA salt. LCMS calculated forC₂₉H₂₄F₂N_(T)O₃ [M+H]⁺ m/z: 556.2; Found: 556.2.

Example 1361-(5-(1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with cyclobutylamine replacing pyrimidin-4-amine.LCMS calculated for C₂₉H₂₈F₂N₅O₃ [M+H]⁺ m/z: 532.2; Found: 532.2.

Example 1371-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-2-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 2-aminopyridine replacing pyrimidin-4-amine.LCMS calculated for C₃₀H₂₅F₂N₆O₃ [M+H]⁺ m/z: 555.2; Found: 555.2.

Example 1381-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 3-aminopyridine replacing pyrimidin-4-amine.LCMS calculated for C₃₀H₂₅F₂N₆O₃ [M+H]⁺ m/z: 555.2; Found: 555.2.

Example 1391-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 2-methoxy ethylamine replacingpyrimidin-4-amine. LCMS calculated for C₂₈H₂₈F₂N₅O₄ [M+H]⁺ m/z: 536.2;Found: 536.2.

Example 1401-(5-(1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with cyclopropylmethyl amine replacingpyrimidin-4-amine. LCMS calculated for C₂₉H₂₈F₂N₅O₃ [M+H]⁺ m/z: 532.2;Found: 532.2.

Example 1413-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1. Preparation ofN-((4-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyanilin

This compound was prepared using procedures analogous to those forExample 135, Step 2 with1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile.LCMS calculated for C₁₈H₁₈ClF₂N₄O₂ [M+H]⁺ m/z: 395.1; Found: 395.1.

Step 2. Preparation of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 135, Step 3 withN-((4-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyanilin(Step 1) replacing1-(4-chloro-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2,3′-bipyridin-6′-yl)cyclobutanecarbonitrile and ethylamine replacingpyrimidin-4-amine. LCMS calculated for C₂₁H₂₂F₂N₅O₃ [M+H]⁺ m/z: 430.2;Found: 430.2.

Example 1424-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile

This compound was prepared using procedures analogous to those forExample 141, Step 2 with 4-amino benzonitrile replacing ethylamine. LCMScalculated for C₂₆H₂₁F₂N₆O₃ [M+H]⁺m/z: 503.2; Found: 503.2.

Example 1433-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 141, Step 2 with (1-ethyl-1H-pyrazol-4-yl)methanamine replacingethylamine. LCMS calculated for C₂₅H₂₆F₂N₇O₃ [M+H]⁺ m/z: 510.2; Found:510.2.

Example 1444-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile

Step 1. Preparation ofN-((4-chloro-6-(1-methyl-H-yl-4-yl)pyrazol-4yl)pyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyanilin

This compound was prepared using procedures analogous to those forExample 135, Step 2 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole replacing1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile.LCMS calculated for C₁₈H₁₈ClF₂N₄O₂ [M+H]⁺ m/z: 395.1; Found: 395.1.

Step 2. Preparation of4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 4-amino benzonitrile replacingpyrimidin-4-amine. LCMS calculated for C₂₆H₂₁F₂N₆O₃ [M+H]⁺ m/z: 503.2;Found: 503.2.

Example 1453-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 144, Step 2 with (1-ethyl-1H-pyrazol-4-yl)methanamine replacing4-amino benzonitrile. LCMS calculated for C₂₅H₂₆F₂N₇O₃ [M+H]⁺ m/z:510.2; Found: 510.2.

TABLE 6 The compounds in Table 6 were prepared in accordance with thesynthetic protocols set forth in Scheme 3 and Example 1, using theappropriate starting materials LCMS Example Name Structure (M + H)+ 1462′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(3-methyl-1-(3-morpholinopropyl)-1H- pyrazol-4-yl)-1′H- spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

554.1 147 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(1-(methylsulfonyl)pyrrolidin-3-yl)- 1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

560.1 148 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(2-(1-(methylsulfonyl)piperidin-4- yl)ethyl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-l,4′- [2,7]naphthyridin]-3′(2′H)-one

602.3 149 1-(4-(2′-(2,6-difluoro-3,5- dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane- 1,4′-[2,7]naphthyridine]-6′-yl)-5-methyl-1H-pyrazol-1- yl)cyclobutanecarbonitrile

506.2 150 6′-(1-(1-acetylpyrrolidin-3-yl)- 1H-pyrazol-4-yl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)- 1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

524.2 151 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(3-morpholinopropyl)-1H-pyrazol- 4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)- one

540.1 152 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(2-(4-methoxypiperidin-1-yl)ethyl)-1H- pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

554.2 153 2-(4-(2′-(2,6-difluoro-3,5- dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane- 1,4′-[2,7]naphthyridine]-6′-yl)-3-methyl-1H-pyrazol-1- yl)acetonitrile

466.2 154 2-(3-(4-(2′-(2,6-difluoro-3,5- dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane- 1,4′-[2,7]naphthyridine]-6′-yl)-3-methyl-1H-pyrazol-1- yl)pyrrolidin-1-yl)acetonitrile

535.1 155 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(3-methyl-1-(pyridin-3-ylmethyl)-1H- pyrazol-4-yl)-1′H- spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

518.1 156 3-(4-(2′-(2,6-difluoro-3,5- dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane- 1,4′-[2,7]naphthyridine]-6′-yl)-3-methyl-1H-pyrazol-1- yl)propanenitrile

480.1 157 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(2-morpholinoethyl)-1H-pyrazol-4- yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

526.2 158 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-1′H- spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

455.1 159 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H- pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

554.2 160 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(2-(dimethylamino)thiazol-4-yl)- 1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

473.1 161 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)- 1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

540.2 162 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-{1-[(1,1-dioxido-1,2-thiazinan-3- yl)methyl]-1H-pyrazol-4-yl}-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

560.1 163 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(3-methyl-1-(1-methylpyrrolidin-3-yl)-1H- pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

510.2 164 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-(2-(dimethylamino)ethyl)-3-methyl- 1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

498.4 165 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(3-methyl-1-(2-(piperidin-4-yl)ethyl)-1H- pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

538.2 166 2′-(2,6-difluoro-3,5- dimethoxyphenyl)-6′-(1-((1-(methylsulfonyl)azetidin-3- yl)methyl)-1H-pyrazol-4-yl)-1′H-spiro[cyclopropane-1,4′- [2,7]naphthyridin]-3′(2′H)-one

560.1 167 6′-(1-((1-acetylazetidin-3- yl)methyl)-1H-pyrazol-4-yl)-2′-(2,6-difluoro-3,5- dimethoxyphenyl)-1′H- spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

524.2

TABLE 7 The compounds in Table 7 were prepared in accordance with thesynthetic protocols set forth in Scheme 4 and Example 22, using theappropriate starting materials LCMS Example Name/¹H NMR Structure (M +H)+ 168 3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-ethyl-7-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)- one:¹H NMR (500 MHz, dmso) δ 8.38 (s, 1H), 8.36 (s, 1H), 7.31 (s, 1H), 7.09(t, J = 8.2 Hz, 1H), 4.83 (s, 2H), 4.14 (q, J = 7.3 Hz, 2H), 4.02 (q, J= 6.9 Hz, 2H), 3.91 (s, 6H), 2.45 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H),1.23 (t, J = 7.0 Hz, 3H).

458.2 169 3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)- one

430.2 170 3-(2,6-difluoro-3,5- dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-ethyl-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)- one

444.2

Example 1715-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazole-4-carbonitrile

Step 1:5-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile

6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one(0.507 g, 1.33 mmol),1-{[2-(trimethylsilyl)ethoxy]methyl})-1H-pyrazole-4-carbonitrile (0.342g, 1.53 mmol), palladium acetate (29.9 mg, 0.133 mmol), trimethylaceticAcid (34.0 mg, 0.333 mmol), potassium carbonate (0.552 g, 4.00 mmol) anddi-1-adamantyl(butyl)phosphine (71.6 mg, 0.200 mmol) were mixed inN,N-dimethylformamide (2.67 mL) and 1,4-dioxane (2.67 mL). The mixturewas heated at 130° C. for 1.5 h. The crude was diluted with DCM, andfiltered through Celite. The filtrate was concentrated. The residue waspurified by chromatography on silica gel (35-60% EtOAc/Hex) to give thedesired coupling product 760 mg (not 100% pure). Rf=0.41 (50%EtOAc/Hex). LC/MS calculated for C₂₈H₃₂F₂N₅O₄Si [M+H]⁺ m/z: 568.2;found: 568.2.

Step 2:5-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazole-4-carbonitrile

Trifluoroacetic acid (0.464 mL, 6.02 mmol) was added to the solution of5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile(171 mg, 0.301 mmol) in DCM. The mixture was stirred at room temperaturefor 15 h. The resulting mixture was concentrated, and NH₄OH in MeOH wasadded. The mixture was stirred at room temperature for 30 min. The crudewas diluted with water and extracted with DCM. The organic phase wasconcentrated. The residue was purified by chromatography on silica gel(4-10% MeOH/DCM) to give the product 49.0 mg. LC/MS calculated forC₂₂H₁₈F₂N₅O₃ [M+H]⁺ m/z: 438.1; found: 438.2.

Example 1723-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1-methyl-1H-pyrazole-4-carbonitrile

Cesium Carbonate (13.1 mg, 0.0402 mmol) was added to the solution of5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]-1H-pyrazole-4-carbonitrile(Example 171: 8.8 mg, 0.020 mmol) in N,N-dimethylformamide (150 μL),followed by methyl iodide (7.14 mg, 0.0503 mmol). The mixture wasstirred at room temperature overnight. The crude was diluted with DCMand filtered. The filtrate was concentrated. The residue was dilutedwith MeOH and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to afford the product as a white solid (TFA salt). LC/MS calculated forC₂₃H₂₀F₂N₅O₃ [M+H]⁺ m/z: 452.2; found: 452.2.

Example 1733-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbonitrile

Cesium Carbonate (10.4 mg, 0.0320 mmol) was added to the solution of5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]-1H-pyrazole-4-carbonitrile(Example 171: 7.0 mg, 0.016 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran(7.16 mg, 0.0400 mmol) in N,N-dimethylformamide (120 μL). The mixturewas stirred at room temperature overnight. The crude was diluted withDCM and filtered. The filtrate was concentrated. The residue was dilutedwith MeOH and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to afford the product as a white solid (TFA salt). LC/MS calculated forC₂₈H₂₈F₂N₅O₄ [M+H]⁺ m/z: 536.2; found: 536.1.

Example 1741-(cyanomethyl)-3-(2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)-1H-pyrazole-4-carbonitrile

Cesium Carbonate (10.4 mg, 0.0320 mmol) was added to the solution of5-[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]-1H-pyrazole-4-carbonitrile(Example 171: 7.0 mg, 0.016 mmol) and bromoacetonitrile (4.80 mg, 0.0400mmol) in N,N-dimethylformamide (120 μL). The mixture was stirred at 40°C. for 2 h. The crude was diluted with DCM and filtered. The filtratewas concentrated. The residue was diluted with MeOH and purified via pH2 preparative LC/MS (MeCN/water with TFA) to afford the product as awhite solid (TFA salt). LC/MS calculated for C₂₄H₁₉F₂N₆O₃ [M+H]⁺ m/z:477.1; found: 477.2.

Example 1755-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-ethylpicolinamide

Step 1:5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinicacid

This compound was prepared using procedures analogous to those forExample 22, Step 2, with 6-(methoxycarbonyl)pyridin-3-ylboronic acidreplacing phenyl boronic acid. LC/MS calculated for C₂₃H₂₁F₂N₄O₅ [M+H]⁺m/z: 471.1; Found: 471.2.

Step 2:5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-ethylpicolinamide

To a mixture of5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinicacid (10 mg, 0.021 mmol) from previous step,Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(11 mg, 0.025 mmol), and Et₃N (15 μL, 0.11 mmol) in DMF (1.5 mL) at rtwas added EtNH₂ (2.0 M in THF, 53 μL, 0.11 mmol). The reaction mixturewas stirred at rt overnight, diluted with MeOH, and directly purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to give the desiredproduct as a white solid (TFA salt). LC/MS calculated for C₂₅H₂₆F₂N₅O₄[M+H]⁺ m/z: 498.2; Found: 498.2. ¹H NMR (600 MHz, DMSO) δ 9.32 (dd,J=2.2, 0.7 Hz, 1H), 8.87 (t, J=6.0 Hz, 1H), 8.67 (dd, J=8.2, 2.2 Hz,1H), 8.46 (s, 1H), 8.15 (dd, J=8.2, 0.7 Hz, 1H), 7.72 (s, 1H), 7.07 (t,J=8.1 Hz, 1H), 4.84 (s, 2H), 4.07 (q, J=7.0 Hz, 2H), 3.90 (s, 6H),3.42-3.32 (m, 2H), 1.23 (t, J=7.0 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H).

Example 176N-cyclopropyl-5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinamide

This compound was prepared using procedures analogous to those forExample 175, Step 2, with cyclopropylamine replacing EtNH₂ (2.0 M inTHF). LC/MS calculated for C₂₆H₂₆F₂N₅O₄ [M+H]⁺ m/z: 510.2; Found: 510.2.

Example 1775-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-(2-hydroxyethyl)picolinamide

This compound was prepared using procedures analogous to those forExample 175, Step 2, with ethanolamine replacing EtNH₂ (2.0 M in THF).LC/MS calculated for C₂₅H₂₆F₂N₅O₅ [M+H]⁺ m/z: 514.2; Found: 514.2.

Example 1785-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-isopropylpicolinamide

This compound was prepared using procedures analogous to those forExample 175, Step 2, with 2-propanamine replacing EtNH₂ (2.0 M in THF).LC/MS calculated for C₂₆H₂₈F₂N₅O₄ [M+H]⁺ m/z: 512.2; Found: 512.2.

Example 1795-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-N-propylpicolinamide

This compound was prepared using procedures analogous to those forExample 175, Step 2, with 1-propanamine replacing EtNH₂ (2.0 M in THF).LC/MS calculated for C₂₆H₂₈F₂N₅O₄ [M+H]⁺ m/z: 512.2; Found: 512.2.

Example 1802-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)phenyl)acetonitrile

This compound was prepared using procedures analogous to those forExample 22, step 2, with 4-(cyanomethyl)phenylboronic acid replacingphenyl boronic acid. LC/MS calculated for C₂₅H₂₃F₂N₄O₃ [M+H]⁺ m/z:465.2; Found: 465.1.

Example 1811-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)phenyl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 22, Step 2, with1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarbonitrilereplacing phenyl boronic acid. LC/MS calculated for C₂₈H₂₇F₂N₄O₃ [M+H]⁺m/z: 505.2; Found: 505.2.

Example 1823-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(6-morpholinopyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

This compound was prepared using procedures analogous to those forExample 22, Step 2, with4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholinereplacing phenyl boronic acid. LC/MS calculated for C₂₆H₂₈F₂N₅O₄ [M+H]⁺m/z: 512.2; Found: 512.2.

Example 1831-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)phenyl)cyclopropanecarbonitrile

This compound was prepared using procedures analogous to those forExample 22, Step 2, with 4-(1-cyanocyclopropyl)phenylboronic acidreplacing phenyl boronic acid. LC/MS calculated for C₂₇H₂₅F₂N₄O₃ [M+H]⁺m/z: 491.2; Found: 491.2.

Example 1845-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinamide

Step 1:5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinonitrile

This compound was prepared using procedures analogous to those forExample 22, Step 2, with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile replacingphenyl boronic acid. LC/MS calculated for C₂₃H₂₀F₂N₅O₃ [M+H]⁺ m/z:452.2; Found: 452.1.

Step 2:5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinamide

A mixture of5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)picolinonitrile(94 mg, 0.21 mmol) in NaOH solution (1.0 M in H₂O) (1.20 mL) and ethanol(3.6 mL) was stirred at 80° C. overnight. The reaction mixture wascooled to rt, quenched with HCl solution (12.0 M in H₂O, 120 μL), andconcentrated. The crude material was then purified via pH 2 preparativeLC/MS (MeCN/water with TFA) to give the desired product as a white solid(TFA salt). LC/MS calculated for C₂₃H₂₂F₂N₅O₄ [M+H]⁺ m/z: 470.2; Found:470.1.

Example 1852′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(pyridin-4-yl)-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

This compound was prepared using procedures analogous to those forExample 1, Step 7, with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine replacing(5-amino-2-methylphenyl)boronic acid. LC/MS calculated for C₂₃H₂₀F₂N₃O₃[M+H]⁺ m/z: 424.1; Found: 424.2.

Example 1862′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-(1-methyl-H-pyrazol-4-yl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

This compound was prepared using procedures analogous to those forExample 1, Step 7, with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing (5-amino-2-methylphenyl)boronic acid. LC/MS calculated forC₂₂H₂₁F₂N₄O₃ [M+H]⁺ m/z: 427.2; Found: 427.1.

Example 1871-(5-{3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl}pyridin-2-yl)cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 1-(5-methyl-1,3,4-oxadiazol-2-yl)methanaminereplacing pyrimidin-4-amine. LCMS calculated for C₂₉H₂₆F₂N₇O₄ [M+H]⁺m/z: 574.2; Found: 574.2.

Example 1881-{5-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl]pyridin-2-yl}cyclobutanecarbonitrile

This compound was prepared using procedures analogous to those forExample 135, Step 3 with 1-methyl-1H-pyrazol-4-amine replacingpyrimidin-4-amine. LCMS calculated for C₂₉H₂₆F₂N₇O₃ [M+H]⁺ m/z: 558.2;Found: 558.1.

Example A

FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was measured in anenzyme assay that measures peptide phosphorylation using FRETmeasurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.5 μL was transferred to the wells of a384-well plate. For FGFR3, a 10 μL volume of FGFR3 enzyme (Millipore)diluted in assay buffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 0.01%Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated fora time between 5-10 minutes and up to 4 hours. Appropriate controls(enzyme blank and enzyme with no inhibitor) were included on the plate.

The assay was initiated by the addition of a 10 μL solution containingbiotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP(final concentrations of 500 nM and 140 μM respectively) in assay bufferto the wells. The plate was incubated at 25° C. for 1 hr. The reactionswere ended with the addition of 10 μL/well of quench solution (50 mMTris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 30 mM EDTA with Perkin ElmerLance Reagents at 3.75 nM Eu-antibody PY20 and 180 nM APC-Streptavidin).The plate was allowed to equilibrate for ˜1 hr before scanning the wellson a PheraStar plate reader (BMG Labtech).

FGFR1, FGFR2, and FGFR4 are measured under equivalent conditions withthe following changes in enzyme and ATP concentrations: FGFR1, 0.02 nMand 210 uM respectively, FGFR2, 0.01 nM and 100 uM, respectively, andFGFR4, 0.04 nM and 600 uM respectively. The enzymes were purchased fromMillipore or Invitrogen.

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.Y=Bottom+(Top−Bottom)/(1+10^((LogIC₅₀−X)*HillSlope)) where X is thelogarithm of concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

The compounds of the invention were found to be selective inhibitors ofFGFR3 and/or FGFR4 according to the FGFR Enzymatic Assays. Compounds ofFormula (I′) and (I) and all the compounds as described herein have beentested and exhibit an IC₅₀ of less than 1 μM.

Table 1 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 4 hours. The symbol: “+” indicates an IC₅₀ lessthan 10 nM; “++” indicates an IC₅₀ greater than or equal to 10 nM butless than 30 nM; “+++” indicates an IC₅₀ greater than or equal to 30 nMbut less than 200 nM; and “++++” indicates an IC₅₀ greater than or equalto 200 nM. Table 2 provides IC₅₀ ratios showing FGFR4 selectivity. Table2A provides IC₅₀ ratios showing FGFR3 selectivity of the compounds.

TABLE 1 Example FGFR1 FGFR2 FGFR3 FGFR4 No. IC50 (nM) IC50 (nM) IC50(nM) IC50 (nM) 1 ++++ ++++ ++++ +++ 2 ++++ ++++ ++++ +++ 3 ++++ ++++++++ ++ 4 +++ +++ +++ + 5 +++ ++ ++ + 6 ++++ ++++ +++ + 7 ++++ ++++ +++++++ 8 ++++ ++++ +++ ++ 9 +++ +++ ++ ++ 10 +++ ++ ++ + 11 ++++ ++++ ++++++ 12 ++++ +++ +++ + 13 ++++ +++ +++ + 14 ++++ +++ +++ + 15 +++ ++++++ + 16 ++++ +++ +++ + 17 ++++ +++ ++ ++ 18 ++ + + ++ 19 ++ + + + 20+++ ++ ++ ++ 21 ++ + + ++ 22 +++ ++ ++ ++ 23 +++ + + + 24 ++ + + ++ 25++ + + ++ 26 ++ + + ++ 27 ++ + + ++ 28 ++++ +++ +++ ++++ 29 ++ + + ++ 30++ + + ++ 31 ++ + + ++ 32 ++ + + ++ 33 +++ + + +++ 34 +++ ++ + +++ 35++ + + ++ 36 ++ + + ++ 37 ++ + + +++ 38 +++ ++ + +++ 39 ++ + + + 40+++ + + +++ 41 +++ ++ ++ +++ 42 ++++ +++ +++ ++++ 43 ++++ +++ ++ +++ 44+++ ++ + +++ 45 +++ ++ + +++ 46 ++ + + ++ 47 +++ + + +++ 48 ++ + + ++ 49+++ + + +++ 50 +++ ++ ++ ++ 51 ++++ +++ +++ ++++ 52 +++ ++ + ++ 53++ + + ++ 54 +++ + + ++ 55 ++ + + + 56 ++++ +++ +++ +++ 57 ++++ +++ +++++ 58 +++ + + ++ 59 +++ ++ ++ +++ 60 +++ ++ + +++ 61 ++++ +++ ++ ++++62 +++ ++ + +++ 63 +++ ++ + +++ 64 +++ ++ + +++ 65 +++ + + +++ 66 +++++++ ++ +++ 67 +++ + + +++ 68 +++ ++ + +++ 69 +++ ++ + +++ 70 +++ ++ +++++ 71 +++ +++ ++ +++ 72 + + + + 73 +++ ++ ++ +++ 74 +++ +++ ++ +++ 75+++ +++ ++ +++ 76 +++ +++ ++ +++ 77 ++ + + +++ 78 +++ ++ + +++ 79+++ + + +++ 80 +++ ++ + +++ 81 +++ ++ ++ ++++ 82 +++ + + +++ 83 +++ +++++ ++++ 84 +++ + + +++ 85 +++ ++ + +++ 86 +++ ++ ++ +++ 87 +++ + + +++88 + + + + 89 ++ + + +++ 90 +++ ++ + +++ 91 +++ + + +++ 92 +++ ++ ++ +++93 +++ + + +++ 94 + + + ++ 95 ++ + + +++ 96 +++ ++ ++ +++ 97 +++ + + +++98 +++ ++ ++ +++ 99 +++ + + +++ 100 +++ ++ ++ +++ 101 + + + ++ 102 +++++ ++ +++ 103 +++ ++ ++ +++ 104 ++ + + +++ 105 +++ ++ ++ +++ 106 +++ +++++ +++ 107 +++ ++ ++ +++ 108 +++ ++ ++ +++ 109 ++ + + +++ 110 ++ + + +++111 ++ + + +++ 112 +++ + + +++ 113 +++ + ++ +++ 114 +++ ++ ++ +++ 115+++ + + +++ 122 +++ ++ ++ +++ 123 +++ + + ++ 124 + + + + 125 +++ + +++++ 129 ++ + + +++ 130 +++ ++ ++ +++ 131 +++ ++ ++ ++++ 132 +++ ++ +++++ 133 ++ + + +++ 134 ++ + + +++ 135 +++ + + +++ 146 +++ ++ + +++ 147++ + + + 148 +++ ++ + ++ 149 +++ + + +++ 150 + + + + 151 + + + + 152++ + + ++ 153 +++ ++ + ++ 154 +++ ++ ++ +++ 155 +++ +++ ++ +++ 156 +++++ + ++ 157 ++ + + + 158 +++ + + ++ 159 +++ ++ ++ +++ 160 ++ + + ++ 161++ + + ++ 162 ++ + + + 163 +++ + + +++ 164 +++ ++ ++ +++ 165 ++ + + ++166 ++ + + ++ 167 + + + ++ 168 ++ + + ++ 169 + + + ++ 170 ++ + + ++ 171+++ +++ +++ + 172 ++++ ++++ ++++ ++ 173 ++++ ++++ ++++ ++ 174 ++++ ++++++++ ++ 175 +++ + + +++ 176 ++ + + ++ 177 ++ + + ++ 178 ++ + + ++ 179++ + + ++ 180 +++ + + ++ 181 +++ + + +++ 182 ++ + + ++ 183 ++ + + +++184 ++ + + ++ 185 ++ + + ++ 186 + + + + 187 +++ + + +++ 188 +++ ++ +++++

TABLE 2 FGFR1/ FGFR2/ FGFR3/ Example No. FGFR4 FGFR4 FGFR4 1 >25 >25 >252 >10 >10 >10 3 >25 >25 >10 4 >25 >10 >10 5 >10 >5 >1 6 >100 >100 >257 >50 >25 >25 8 >50 >10 >10 9 >10 >1 >1 10 >25 >25 >10 11 >25 >25 >1012 >50 >25 >10 13 >50 >25 >10 14 >50 >10 >1 15 >50 >25 >1016 >50 >25 >10 171 >10 >10 >10 172 >50 >25 >10 173 >100 >100 >50174 >100 >10 >25

TABLE 2A FGFR1/ FGFR4/ Example No. FGFR3 FGFR3 4 >1 5 >3 6 >3 7 >1 8 >59 >3 10 >1 11 >1 12 >3 13 >3 14 >5 15 >3 16 >1 17 >10 18 >5 19 >5 20 >521 >5 22 >5 23 >5 24 >5 25 >5 >5 26 >5 >5 27 >10 >10 28 >10 >25 29 >1 >530 >1 >5 31 >5 >10 32 >1 >5 33 >5 >5 34 >5 >10 35 >5 >10 36 >5 >1037 >1 >10 38 >5 >5 39 >10 >10 40 >10 >10 41 >1 >5 42 >5 >1 43 >10 >544 >10 >10 45 >10 >10 46 >10 >10 47 >10 >10 48 >10 >10 49 >5 >1 50 >1 >151 >1 >1 52 >10 >1 53 >5 >5 54 >5 >1 55 >10 >5 56 >5 >1 57 >10 >1058 >10 >10 59 >10 >10 60 >10 >5 61 >10 >5 62 >10 >5 63 >10 >5z64 >10 >10 65 >5 >10 66 >5 >5 67 >5 >10 68 >5 >5 69 >5 >5 70 >5 >571 >5 >3 72 >5 >10 73 >5 >10 74 >5 >5 75 >5 >3 76 >5 >5 77 >5 >1078 >5 >3 79 >5 >3 80 >5 >10 81 >5 >10 82 >5 >5 83 >5 >5 84 >5 >585 >5 >10 86 >5 >10 87 >5 >10 88 >5 >10 89 >5 >10 90 >5 >5 91 >5 >592 >5 >10 93 >5 >5 94 >5 >10 95 >5 >10 96 >5 >5 97 >5 >10 98 >5 >1099 >5 >5 100 >5 >5 101 >5 >10 102 >3 >10 103 >3 >5 104 >3 >5 105 >3 >5106 >3 >5 107 >3 >10 108 >3 >3 109 >3 >10 110 >3 >5 111 >3 >5 112 >3 >5113 >3 >5 114 >3 >5 115 >3 >5 122 >5 >5 123 >5 >3 124 >10 >10 125 >5 >5129 >5 >10 130 >5 >5 131 >3 >10 132 >3 >5 133 >3 >5 134 >3 >5 135 >5 >10146 >10 >5 147 >10 >3 148 >10 >3 149 >5 >3 150 >5 >5 151 >5 >5 152 >5 >3153 >5 >3 154 >5 >3 155 >5 >1 156 >5 >1 157 >5 >3 158 >5 >3 159 >5 >3160 >5 >5 161 >5 >3 162 >5 >1 163 >3 >3 164 >3 >3 165 >3 >3 166 >3 >3167 >3 >3 168 >5 >3 169 >3 >5 170 >3 >5 175 >10 >5 176 >10 >5 177 >5 >10178 >5 >5 179 >5 >10 180 >5 >5 181 >5 >10 182 >5 >5 183 >3 >10 184 >5 >5185 >3 >3 186 >5 >5 187 >10 >10 188 >5 >5

Table 3 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 5 to 10 minutes. The symbol: “+” indicates an IC₅₀less than 10 nM; “++” indicates an IC₅₀ greater than or equal to 10 nMbut less than 30 nM; “+++” indicates an IC₅₀ greater than or equal to 30nM but less than 200 nM; and “++++” indicates an IC₅₀ greater than orequal to 200 nM. Table 4 provides ratios of IC₅₀ data, showing FGFR4selectivity.

TABLE 3 Example FGFR1 FGFR2 FGFR3 FGFR4 No. IC50 (nM) IC50 (nM) IC50(nM) IC50 (nM) 1 ++++ ++++ ++++ +++ 2 ++++ ++++ ++++ +++ 3 ++++ ++++++++ ++ 4 +++ ++ ++ + 5 +++ ++ ++ + 6 ++++ ++++ +++ + 7 ++++ ++++ +++++++ 8 ++++ ++++ +++ ++ 9 +++ ++ +++ ++ 10 +++ ++ ++ + 11 ++++ ++++ +++++ 12 ++++ +++ +++ + 13 ++++ +++ +++ + 14 ++++ +++ ++ + 15 +++ +++ +++ +16 ++++ +++ +++ + 57 +++ +++ ++ ++++ 58 ++ + + ++ 59 +++ ++ ++ +++ 69+++ + + +++ 116 ++ + + ++ 117 +++ ++ ++ +++ 118 +++ ++ ++ +++ 119 ++ + +++ 120 +++ ++ ++ +++ 121 ++ + + +++ 126 ++ + + +++ 127 +++ ++ ++ +++128 + + + ++ 136 +++ ++ ++ +++ 137 +++ ++ ++ +++ 138 +++ ++ ++ +++ 139+++ + + +++ 140 +++ + ++ +++ 141 +++ ++ + +++ 142 +++ +++ ++ +++ 143 +++++ + +++ 144 +++ ++ ++ +++ 145 + + + ++ 168 ++ + + ++ 169 + + + ++ 170++ + + ++ 175 ++ + + ++ 186 + + + + 187 ++ + + +++

TABLE 4 FGFR1/ FGFR2/ FGFR3/ Example No. FGFR4 FGFR4 FGFR4 1 >25 >25 >502 >10 >10 >10 3 >25 >25 >25 4 >10 >10 >5 5 >10 >5 >4 6 >100 >100 >507 >25 >10 >10 8 >50 >10 >10 9 >5 >1 >1 10 >25 >10 >10 11 >50 >20 >2512 >50 >25 >20 13 >50 >20 >10 14 >25 >5 >5 15 >50 >25 >10 16 >25 >10 >10

Example B

FGFR4 Cellular and In Vivo Assays

The FGFR4 inhibitory activity of the example compounds in cells,tissues, and/or animals can be demonstrated according to one or moreassays or models described in the art such as, for example, in French etal. “Targeting FGFR4 Inhibits Hepatocellular Carcinoma in PreclinicalMouse Models,” PLoS ONE, May 2012, Vol. 7, Issue 5, e36713, which isincorporated herein by reference in its entirety.

Example C

Cell-Based FGFR Phosphorylation Assays

The inhibitory effect of compounds on FGFR phosphorylation in relevantcell lines (Ba/F3-FGFR3, KMS-11, RT112, KatoIII, H-1581 cancer celllines and HUVEC cell line) can be assessed using immunoassays specificfor FGFR phosphorylation. Cells are starved in media with reduced serum(0.5%) and no FGF1 for 4 to 18 h depending upon the cell line thentreated with various concentrations of individual inhibitors for 1-4hours. For some cell lines, such as Ba/F3-FGFR3 and KMS-11, cells arestimulated with Heparin (20 μg/mL) and FGF1 (10 ng/mL) for 10 min. Wholecell protein extracts are prepared by incubation in lysis buffer withprotease and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl,1.5 mM MgCl₂, 10% Glycerol, 1% Triton X-100, 1 mM sodium orthovanadate,1 mM sodium fluoride, aprotinin (2 g/mL), leupeptin (2 μg/mL), pepstatinA (2 μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4° C. Proteinextracts are cleared of cellular debris by centrifugation at 14,000×gfor 10 minutes and quantified using the BCA (bicinchoninic acid)microplate assay reagent (Thermo Scientific).

Phosphorylation of FGFR receptor in protein extracts was determinedusing immunoassays including western blotting, enzyme-linked immunoassay(ELISA) or bead-based immunoassays (Luminex). For detection ofphosphorylated FGFR2, a commercial ELISA kit DuoSet IC Human Phospho-FGFR2α ELISA assay (R&D Systems, Minneapolis, Minn.) can be used. For theassay Katoll cells are plated in 0.2% FBS supplemented Iscove's medium(50,000 cells/well/per 100 μL) into 96-well flat-bottom tissue culturetreated plates (Corning, Corning, N.Y.), in the presence or absence of aconcentration range of test compounds and incubated for 4 hours at 37°C., 5% CO₂. The assay is stopped with addition of 200 μL of cold PBS andcentrifugation. The washed cells are lysed in Cell Lysis Buffer (CellSignaling, #9803) with Protease Inhibitor (Calbiochem, #535140) and PMSF(Sigma, #P7626) for 30 min on wet ice. Cell lysates were frozen at −80OC before testing an aliquot with the DuoSet IC Human Phospho-FGFR2αELISA assay kit. GraphPad prism3 was used to analyze the data. TheIC₅₀ values were derived by fitting the data to the equation for asigmoidal dose-response with a variable slope.

For detection of phosphorylated FGFR3, a bead based immunoassay wasdeveloped. An anti-human FGFR3 mouse mAb (R&D Systems, cat#MAB7661) wasconjugated to Luminex MAGplex microspheres, bead region 20 and used asthe capture antibody. RT-112 cells were seeded into multi-well tissueculture plates and cultured until 70% confluence. Cells were washed withPBS and starved in RPMI+0.5% FBS for 18 hr. The cells were treated with10 μL of 10× concentrations of serially diluted compounds for 1 hr at37° C., 5% CO₂ prior to stimulation with 10 ng/mL human FGF1 and 20μg/mL Heparin for 10 min. Cells were washed with cold PBS and lysed withCell Extraction Buffer (Invitrogen) and centrifuged. Clarifiedsupernatants were frozen at −80° C. until analysis.

For the assay, cell lysates are diluted 1:10 in Assay Diluent andincubated with capture antibody-bound beads in a 96-well filter platefor 2 hours at room temperature on a plate shaker. Plates are washedthree times using a vacuum manifold and incubated with anti-phospho-FGFR1-4 (Y653/Y654) rabbit polyclonal antibody (R&D Systems cat# AF3285)for 1 hour at RT with shaking. Plates are washed three times. Thediluted reporter antibody, goat anti-rabbit-RPE conjugated antibody(Invitrogen Cat. # LHB0002) is added and incubated for 30 minutes withshaking. Plates are washed three times. The beads are suspended in washbuffer with shaking at room temperature for 5 minutes and then read on aLuminex 200 instrument set to count 50 events per sample, gate settings7500-13500. Data is expressed as mean fluorescence intensity (MFI). MFIfrom compound treated samples are divided by MFI values from DMSOcontrols to determine the percent inhibition, and the IC₅₀ values arecalculated using the GraphPad Prism software. Compounds having an IC₅₀of 1 μM or less are considered active.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A method for treating bladder cancer in apatient, said method comprising: administering to said patient in needthereof a therapeutically effective amount of a compound, which is3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-pyrimidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-oneor a pharmaceutically acceptable salt thereof.